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Claudia Goettsch
Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

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Corrected proof
Published: 22 February 2021 in Cardiovascular Research
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Aims Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release and incorporation of trafficking vesicles mediates protein secretion and degradation. We hypothesized that ER remodeling that drives mitochondrial fission participates in cardiometabolic proteostasis. Methods and results We used in vitro and in vivo hepatocyte inhibition of a protein involved in mitochondrial fission, dynamin-related protein 1 (DRP1). Here, we show that DRP1 promotes remodeling of select ER microdomains by tethering vesicles at ER. A DRP1 inhibitor, mitochondrial division inhibitor 1 (mdivi-1) reduced ER localization of a DRP1 receptor, mitochondrial fission factor, suppressing ER remodeling-driven mitochondrial fission, autophagy, and increased mitochondrial calcium buffering and PCSK9 proteasomal degradation. DRP1 inhibition by CRISPR/Cas9 deletion or mdivi-1 alone or in combination with statin incubation in human hepatocytes and hepatocyte-specific Drp1-deficiency in mice reduced PCSK9 secretion (−78.5%). In HepG2 cells, mdivi-1 increased low-density lipoprotein receptor via c-Jun transcription and reduced PCSK9 mRNA levels via suppressed sterol regulatory binding protein-1c. Additionally, mdivi-1 reduced macrophage burden, oxidative stress, and advanced calcified atherosclerotic plaque in aortic roots of diabetic Apoe-deficient mice and inflammatory cytokine production in human macrophages. Conclusions We propose a novel tethering function of DRP1 beyond its established fission function, with DRP1-mediated ER remodeling likely contributing to ER constriction of mitochondria that drives mitochondrial fission. We report that DRP1-driven remodeling of select ER micro-domains may critically regulate hepatic proteostasis and identify mdivi-1 as a novel small molecule PCSK9 inhibitor.

ACS Style

Maximillian A Rogers; Joshua D Hutcheson; Takehito Okui; Claudia Goettsch; Sasha A Singh; Arda Halu; Florian Schlotter; Hideyuki Higashi; Lixiang Wang; Mary C Whelan; Andrew K Mlynarchik; Alan Daugherty; Masatoshi Nomura; Masanori Aikawa; Elena Aikawa. Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion. Cardiovascular Research 2021, 1 .

AMA Style

Maximillian A Rogers, Joshua D Hutcheson, Takehito Okui, Claudia Goettsch, Sasha A Singh, Arda Halu, Florian Schlotter, Hideyuki Higashi, Lixiang Wang, Mary C Whelan, Andrew K Mlynarchik, Alan Daugherty, Masatoshi Nomura, Masanori Aikawa, Elena Aikawa. Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion. Cardiovascular Research. 2021; ():1.

Chicago/Turabian Style

Maximillian A Rogers; Joshua D Hutcheson; Takehito Okui; Claudia Goettsch; Sasha A Singh; Arda Halu; Florian Schlotter; Hideyuki Higashi; Lixiang Wang; Mary C Whelan; Andrew K Mlynarchik; Alan Daugherty; Masatoshi Nomura; Masanori Aikawa; Elena Aikawa. 2021. "Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion." Cardiovascular Research , no. : 1.

Journal article
Published: 24 September 2020 in Cells
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Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the developed world, yet no pharmacological therapy exists. Here, we hypothesize that the integration of multiple omic data represents an approach towards unveiling novel molecular networks in CAVD. Databases were searched for CAVD omic studies. Differentially expressed molecules from calcified and control samples were retrieved, identifying 32 micro RNAs (miRNA), 596 mRNAs and 80 proteins. Over-representation pathway analysis revealed platelet degranulation and complement/coagulation cascade as dysregulated pathways. Multi-omics integration of overlapping proteome/transcriptome molecules, with the miRNAs, identified a CAVD protein–protein interaction network containing seven seed genes (apolipoprotein A1 (APOA1), hemoglobin subunit β (HBB), transferrin (TF), α-2-macroglobulin (A2M), transforming growth factor β-induced protein (TGFBI), serpin family A member 1 (SERPINA1), lipopolysaccharide binding protein (LBP), inter-α-trypsin inhibitor heavy chain 3 (ITIH3) and immunoglobulin κ constant (IGKC)), four input miRNAs (miR-335-5p, miR-3663-3p, miR-21-5p, miR-93-5p) and two connector genes (amyloid beta precursor protein (APP) and transthyretin (TTR)). In a metabolite–gene–disease network, Alzheimer’s disease exhibited the highest degree of betweenness. To further strengthen the associations based on the multi-omics approach, we validated the presence of APP and TTR in calcified valves from CAVD patients by immunohistochemistry. Our study suggests a novel molecular CAVD network potentially linked to the formation of amyloid-like structures. Further investigations on the associated mechanisms and therapeutic potential of targeting amyloid-like deposits in CAVD may offer significant health benefits.

ACS Style

Marina A. Heuschkel; Nikolaos T. Skenteris; Joshua D. Hutcheson; Dewy D. Van Der Valk; Juliane Bremer; Philip Goody; Jesper Hjortnaes; Felix Jansen; Carlijn V.C. Bouten; Antoon Van Den Bogaerdt; Ljubica Matic; Nikolaus Marx; Claudia Goettsch. Integrative Multi-Omics Analysis in Calcific Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like Deposits. Cells 2020, 9, 2164 .

AMA Style

Marina A. Heuschkel, Nikolaos T. Skenteris, Joshua D. Hutcheson, Dewy D. Van Der Valk, Juliane Bremer, Philip Goody, Jesper Hjortnaes, Felix Jansen, Carlijn V.C. Bouten, Antoon Van Den Bogaerdt, Ljubica Matic, Nikolaus Marx, Claudia Goettsch. Integrative Multi-Omics Analysis in Calcific Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like Deposits. Cells. 2020; 9 (10):2164.

Chicago/Turabian Style

Marina A. Heuschkel; Nikolaos T. Skenteris; Joshua D. Hutcheson; Dewy D. Van Der Valk; Juliane Bremer; Philip Goody; Jesper Hjortnaes; Felix Jansen; Carlijn V.C. Bouten; Antoon Van Den Bogaerdt; Ljubica Matic; Nikolaus Marx; Claudia Goettsch. 2020. "Integrative Multi-Omics Analysis in Calcific Aortic Valve Disease Reveals a Link to the Formation of Amyloid-Like Deposits." Cells 9, no. 10: 2164.

Journal article
Published: 01 September 2020 in Journal of Biological Chemistry
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In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. In vitro, both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD–mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT 4.54 vs. CatA-TG 8.62 μmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT 19.8 vs. CatA-TG 21.9 μm), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and pro-fibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I:type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight:body weight ratio and LV enddiastolic volume (WT 50.8 vs. CatA-TG 61.9 μl). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling.

ACS Style

Mathias Hohl; Manuel Mayr; Lisa Lang; Alexander G. Nickel; Javier Barallobre-Barreiro; Xiaoke Yin; Thimoteus Speer; Simina-Ramona Selejan; Claudia Goettsch; Katharina Erb; Claudia Fecher-Trost; Jan-Christian Reil; Benedikt Linz; Sven Ruf; Thomas Hübschle; Christoph Maack; Michael Böhm; Thorsten Sadowski; Dominik Linz. Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice. Journal of Biological Chemistry 2020, 295, 12605 -12617.

AMA Style

Mathias Hohl, Manuel Mayr, Lisa Lang, Alexander G. Nickel, Javier Barallobre-Barreiro, Xiaoke Yin, Thimoteus Speer, Simina-Ramona Selejan, Claudia Goettsch, Katharina Erb, Claudia Fecher-Trost, Jan-Christian Reil, Benedikt Linz, Sven Ruf, Thomas Hübschle, Christoph Maack, Michael Böhm, Thorsten Sadowski, Dominik Linz. Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice. Journal of Biological Chemistry. 2020; 295 (36):12605-12617.

Chicago/Turabian Style

Mathias Hohl; Manuel Mayr; Lisa Lang; Alexander G. Nickel; Javier Barallobre-Barreiro; Xiaoke Yin; Thimoteus Speer; Simina-Ramona Selejan; Claudia Goettsch; Katharina Erb; Claudia Fecher-Trost; Jan-Christian Reil; Benedikt Linz; Sven Ruf; Thomas Hübschle; Christoph Maack; Michael Böhm; Thorsten Sadowski; Dominik Linz. 2020. "Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice." Journal of Biological Chemistry 295, no. 36: 12605-12617.

Review
Published: 02 July 2020 in Cells
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Extracellular vesicles (EVs) mediate cell-to-cell communication via the transfer of biomolecules locally and systemically between organs. It has been elucidated that the specific EV cargo load is fundamental for cellular response upon EV delivery. Therefore, revealing the specific molecular machinery that functionally regulates the precise EV cargo intracellularly is of importance in understanding the role of EVs in physiology and pathophysiology and conveying therapeutic use. The purpose of this review is to summarize recent findings on the general rules, as well as specific modulator motifs governing EV cargo loading. Finally, we address available information on potential therapeutic strategies to alter cargo loading.

ACS Style

Bilal Mir; Claudia Goettsch. Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo. Cells 2020, 9, 1601 .

AMA Style

Bilal Mir, Claudia Goettsch. Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo. Cells. 2020; 9 (7):1601.

Chicago/Turabian Style

Bilal Mir; Claudia Goettsch. 2020. "Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo." Cells 9, no. 7: 1601.

Chapter
Published: 02 July 2020 in Contemporary Cardiology
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Bone is a complex and dynamic tissue that, in addition to its biomechanical properties, harbors stem cells and precursor cells of the hematopoietic and immune system. The skeleton undergoes continuous remodeling processes to maintain proper bone homeostasis. The equilibrium and coupling of bone resorption with bone formation is fine-tuned by the controlled actions of distinct cell types: bone-forming osteoblasts, bone-resorbing osteoclasts, and osteocytes as key communicators. This ensures proper bone mass and quality. Under pathophysiological conditions, the impairment of these mechanisms triggers bone remodeling dysregulation, causing loss in bone mass and/or alteration in bone microarchitecture. This chapter deals with the function and regulation of cellular contributors of bone homeostasis – osteoblasts, osteoclasts, osteocytes, and immune cells. Further, we discuss current knowledge on the coupling of bone resorption and bone formation. Finally, we give an overview about the role of inter-organ crosstalk through bone-secreted factors that act as communicators to peripheral organs.

ACS Style

Martina Rauner; Katharina Jähn; Haniyeh Hemmatian; Juliane Colditz; Claudia Goettsch. Cellular Contributors to Bone Homeostasis. Contemporary Cardiology 2020, 333 -371.

AMA Style

Martina Rauner, Katharina Jähn, Haniyeh Hemmatian, Juliane Colditz, Claudia Goettsch. Cellular Contributors to Bone Homeostasis. Contemporary Cardiology. 2020; ():333-371.

Chicago/Turabian Style

Martina Rauner; Katharina Jähn; Haniyeh Hemmatian; Juliane Colditz; Claudia Goettsch. 2020. "Cellular Contributors to Bone Homeostasis." Contemporary Cardiology , no. : 333-371.

Review
Published: 14 March 2020 in Toxins
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Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the ‘point of no return’. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

ACS Style

Anika Himmelsbach; Carina Ciliox; Claudia Goettsch. Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities. Toxins 2020, 12, 181 .

AMA Style

Anika Himmelsbach, Carina Ciliox, Claudia Goettsch. Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities. Toxins. 2020; 12 (3):181.

Chicago/Turabian Style

Anika Himmelsbach; Carina Ciliox; Claudia Goettsch. 2020. "Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities." Toxins 12, no. 3: 181.

Journal article
Published: 03 July 2019 in Toxins
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Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on complement component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.

ACS Style

Marieke Sternkopf; Sven Thoröe-Boveleth; Tobias Beck; Kirsten Oleschko; Ansgar Erlenkötter; Ulrich Tschulena; Sonja Steppan; Thimoteus Speer; Claudia Goettsch; Vera Jankowski; Joachim Jankowski; Heidi Noels; The European Uremic Toxin Work Group-EUTox. A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients. Toxins 2019, 11, 389 .

AMA Style

Marieke Sternkopf, Sven Thoröe-Boveleth, Tobias Beck, Kirsten Oleschko, Ansgar Erlenkötter, Ulrich Tschulena, Sonja Steppan, Thimoteus Speer, Claudia Goettsch, Vera Jankowski, Joachim Jankowski, Heidi Noels, The European Uremic Toxin Work Group-EUTox. A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients. Toxins. 2019; 11 (7):389.

Chicago/Turabian Style

Marieke Sternkopf; Sven Thoröe-Boveleth; Tobias Beck; Kirsten Oleschko; Ansgar Erlenkötter; Ulrich Tschulena; Sonja Steppan; Thimoteus Speer; Claudia Goettsch; Vera Jankowski; Joachim Jankowski; Heidi Noels; The European Uremic Toxin Work Group-EUTox. 2019. "A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients." Toxins 11, no. 7: 389.

Review
Published: 24 October 2018 in Scientific Reports
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Cardiovascular diseases are the main cause of death worldwide, demanding new treatments and interventions. Recently, extracellular vesicles (EVs) came in focus as important carriers of protective molecules such as miRNAs and proteins which might contribute to e.g. improved cardiac function after myocardial infarction. EVs can be secreted from almost every cell type in the human body and can be transferred via the bloodstream in almost every compartment. To provide an all-encompassing overview of studies investigating these beneficial properties of EVs we performed a systematic review/meta-analysis of studies investigating the cardioprotective characteristics of EVs. Forty-three studies were investigated and catalogued according to the EV source. We provide an in-depth analysis of the purification method, size of the EVs, the conducted experiments to investigate the beneficial properties of EVs as well as the major effector molecule encapsulated in EVs mediating protection. This study provides evidence that EVs from different cell types and body fluids provide cardioprotection in different in vivo and in vitro studies. A meta-analysis was performed to estimate the underlying effect size. In conclusion, we demonstrated that EVs from different sources might serve as a promising tool for treating cardiovascular diseases in the future.

ACS Style

Sebastian Wendt; Andreas Goetzenich; Claudia Goettsch; Christian Stoppe; Christian Bleilevens; Sandra Kraemer; Carina Benstoem. Evaluation of the cardioprotective potential of extracellular vesicles – a systematic review and meta-analysis. Scientific Reports 2018, 8, 1 -14.

AMA Style

Sebastian Wendt, Andreas Goetzenich, Claudia Goettsch, Christian Stoppe, Christian Bleilevens, Sandra Kraemer, Carina Benstoem. Evaluation of the cardioprotective potential of extracellular vesicles – a systematic review and meta-analysis. Scientific Reports. 2018; 8 (1):1-14.

Chicago/Turabian Style

Sebastian Wendt; Andreas Goetzenich; Claudia Goettsch; Christian Stoppe; Christian Bleilevens; Sandra Kraemer; Carina Benstoem. 2018. "Evaluation of the cardioprotective potential of extracellular vesicles – a systematic review and meta-analysis." Scientific Reports 8, no. 1: 1-14.

Journal article
Published: 20 September 2018 in Respiratory Research
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Fibroblast growth factor 23 (FGF23) regulates phosphate metabolism by increasing renal phosphate excretion and decreasing 1.25-dihydroxyvitamin D synthesis. Reports about hypophosphatemia in patients with chronic obstructive pulmonary disease (COPD) suggest altered phosphate metabolism. Therefore, we hypothesized that disturbances in phosphate-regulatory hormones such as FGF23 and parathyroid hormone (PTH) are present in COPD patients. We investigated 40 COPD patients (63.5 ± 9.9 years, 27 male), each matched with two age- and sex-matched controls without any primary lung disease. COPD patients underwent lung function testing in advance. All patients had a glomerular filtration rate (GFR) > 60 mL/min/1.73m2. We measured concentrations of intact FGF23 (iFGF23) and c-terminal FGF23 (c-term FGF23), phosphate, parathyroid hormone (PTH) and C-reactive protein (CRP) levels in COPD patients and controls. Phosphate (1.0 ± 02 vs. 1.1 ± 0.2 mmol/L; p = 0.027), PTH (54.2 ± 29.4 vs. 68.7 ± 31.8 pg/mL; p = 0.002) and iFGF23 (46.3 ± 29.0 vs. 57.5 ± 33.5 pg/mL; p = 0.026 ) levels were significantly lower in COPD patients compared with controls. There was a significant negative correlation between c-term FGF23 and total lung capacity (r = - 0.4; p = 0.01), and between c-term FGF23 and CRP in COPD patients (r = 0.48; p = 0.002). iFGF23 and c-term FGF23 were positively correlated with phosphate and PTH in the control group. We confirmed lower average serum phosphate levels in COPD patients compared with controls. However, our data do not suggest a causative role for FGF23 or PTH in COPD because levels of both phosphate-lowering hormones appear to be adaptively decreased as well. Therefore, further investigations are needed to identify the pathogenesis of low phosphate levels in patients with COPD and the relationship between phosphate-regulatory hormones and disease progression.

ACS Style

Alexandra Stroda; Vincent Brandenburg; Ayham Daher; Christian Cornelissen; Claudia Goettsch; András Keszei; Michael Dreher. Serum phosphate and phosphate-regulatory hormones in COPD patients. Respiratory Research 2018, 19, 183 .

AMA Style

Alexandra Stroda, Vincent Brandenburg, Ayham Daher, Christian Cornelissen, Claudia Goettsch, András Keszei, Michael Dreher. Serum phosphate and phosphate-regulatory hormones in COPD patients. Respiratory Research. 2018; 19 (1):183.

Chicago/Turabian Style

Alexandra Stroda; Vincent Brandenburg; Ayham Daher; Christian Cornelissen; Claudia Goettsch; András Keszei; Michael Dreher. 2018. "Serum phosphate and phosphate-regulatory hormones in COPD patients." Respiratory Research 19, no. 1: 183.

Journal article
Published: 21 March 2018 in European Heart Journal
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A new Transregional Collaborative Research Center of the German Research Foundation (DFG) has been created to address reno-cardiovascular interactions underlying the increased cardiovascular risk in patients with chronic kidney disease to develop novel treatment strategies to reduce cardiovascular morbidity and mortality in these high-risk patients

ACS Style

Heidi Noels; Peter Boor; Claudia Goettsch; Mathias Hohl; Wilhelm Jahnen-Dechent; Vera Jankowski; Ingrid Kindermann; Rafael Kramann; Michael Lehrke; Dominik Linz; Christoph Maack; Barbara Niemeyer; Letícia P Roma; Katharina Schuett; Thimoteus Speer; Stefan Wagenpfeil; Christian Werner; Stephen Zewinger; Michael Böhm; Nikolaus Marx; Jürgen Floege; Danilo Fliser; Joachim Jankowski. The new SFB/TRR219 Research Centre. European Heart Journal 2018, 39, 975 -977.

AMA Style

Heidi Noels, Peter Boor, Claudia Goettsch, Mathias Hohl, Wilhelm Jahnen-Dechent, Vera Jankowski, Ingrid Kindermann, Rafael Kramann, Michael Lehrke, Dominik Linz, Christoph Maack, Barbara Niemeyer, Letícia P Roma, Katharina Schuett, Thimoteus Speer, Stefan Wagenpfeil, Christian Werner, Stephen Zewinger, Michael Böhm, Nikolaus Marx, Jürgen Floege, Danilo Fliser, Joachim Jankowski. The new SFB/TRR219 Research Centre. European Heart Journal. 2018; 39 (12):975-977.

Chicago/Turabian Style

Heidi Noels; Peter Boor; Claudia Goettsch; Mathias Hohl; Wilhelm Jahnen-Dechent; Vera Jankowski; Ingrid Kindermann; Rafael Kramann; Michael Lehrke; Dominik Linz; Christoph Maack; Barbara Niemeyer; Letícia P Roma; Katharina Schuett; Thimoteus Speer; Stefan Wagenpfeil; Christian Werner; Stephen Zewinger; Michael Böhm; Nikolaus Marx; Jürgen Floege; Danilo Fliser; Joachim Jankowski. 2018. "The new SFB/TRR219 Research Centre." European Heart Journal 39, no. 12: 975-977.

Review article
Published: 01 January 2018 in Arteriosclerosis, Thrombosis, and Vascular Biology
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Cardiovascular disease is a leading cause of morbidity and mortality in the Western world. Studies of sortilin's influence on cardiovascular and metabolic diseases goes far beyond the genome-wide association studies that have revealed an association between cardiovascular diseases and the 1p13 locus that encodes sortilin. Emerging evidence suggests a significant role of sortilin in the pathogenesis of vascular and metabolic diseases; this includes type II diabetes mellitus via regulation of insulin resistance, atherosclerosis through arterial wall inflammation and calcification, and dysregulated lipoprotein metabolism. Sortilin is also known for its functional role in neurological disorders. It serves as a key receptor for cytokines, lipids, and enzymes and participates in pathological cargo loading to and trafficking of extracellular vesicles. This article provides a comprehensive review of sortilin's contributions to cardiovascular and metabolic diseases but focuses particularly on atherosclerosis. We summarize recent clinical findings that suggest that sortilin may be a cardiovascular risk biomarker and also discuss sortilin as a potential drug target.

ACS Style

Claudia Goettsch; Mads Kjolby; Elena Aikawa. Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. Arteriosclerosis, Thrombosis, and Vascular Biology 2018, 38, 19 -25.

AMA Style

Claudia Goettsch, Mads Kjolby, Elena Aikawa. Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018; 38 (1):19-25.

Chicago/Turabian Style

Claudia Goettsch; Mads Kjolby; Elena Aikawa. 2018. "Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases." Arteriosclerosis, Thrombosis, and Vascular Biology 38, no. 1: 19-25.

Research article
Published: 21 July 2017 in Circulation Research
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Rationale: Mitochondrial changes occur during cell differentiation and cardiovascular disease. DRP1 (dynamin-related protein 1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. Objective: To examine the effects of osteogenic promoting conditions on DRP1 and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results: DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells increased DRP1 expression. DRP1 inhibition in human smooth muscle cells undergoing osteogenic differentiation attenuated matrix mineralization, cytoskeletal rearrangement, mitochondrial dysfunction, and reduced type 1 collagen secretion and alkaline phosphatase activity. DRP1 protein was observed in calcified human aortic valves, and DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 deletion did not exhibit altered vascular pathology in a proprotein convertase subtilisin/kexin type 9 gain-of-function atherosclerosis model. However, when mineralization was induced via oxidative stress, DRP1 inhibition attenuated mouse and human smooth muscle cell calcification. Femur bone density was unchanged in mice heterozygous for Drp1 deletion, and DRP1 inhibition attenuated oxidative stress–mediated dysfunction in human bone osteoblasts. Conclusions: We demonstrate a new function of DRP1 in regulating collagen secretion and cardiovascular calcification, a novel area of exploration for the potential development of new therapies to modify cellular fibrocalcific response in cardiovascular diseases. Our data also support a role of mitochondrial dynamics in regulating oxidative stress–mediated arterial calcium accrual and bone loss.

ACS Style

Maximillian Rogers; Natalia Maldonado; Joshua D. Hutcheson; Claudia Goettsch; Shinji Goto; Iwao Yamada; Tyler Faits; Hiromi Sesaki; Masanori Aikawa; Elena Aikawa. Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress. Circulation Research 2017, 121, 220 -233.

AMA Style

Maximillian Rogers, Natalia Maldonado, Joshua D. Hutcheson, Claudia Goettsch, Shinji Goto, Iwao Yamada, Tyler Faits, Hiromi Sesaki, Masanori Aikawa, Elena Aikawa. Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress. Circulation Research. 2017; 121 (3):220-233.

Chicago/Turabian Style

Maximillian Rogers; Natalia Maldonado; Joshua D. Hutcheson; Claudia Goettsch; Shinji Goto; Iwao Yamada; Tyler Faits; Hiromi Sesaki; Masanori Aikawa; Elena Aikawa. 2017. "Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress." Circulation Research 121, no. 3: 220-233.

Research article
Published: 01 May 2017 in Arteriosclerosis, Thrombosis, and Vascular Biology
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Objective— Genome-wide association studies and preclinical studies demonstrated a role of sortilin in lipid metabolism, inflammation, and vascular calcification—all cardiovascular risk factors. We evaluated the association of serum sortilin levels with the risk of major adverse cerebrovascular and cardiovascular events (MACCE) and the severity of abdominal aortic calcification (AAC). Approach and Results— A cohort of community-dwelling men aged ≥50 years (n=830) was assessed. At baseline, sortilin levels were measured by ELISA, and AAC was assessed on lateral spine scans obtained by dual-energy X-ray absorptiometry. Men aged ≥60 years (n=745) were followed up prospectively for the incidence of MACCE. During the median follow-up of 7.9 years, 76 MACCE occurred. The unadjusted incidence of MACCE across increasing sortilin quartiles was 8.0, 7.4, 19.8, and 20.3 per 1000 person-years. In multivariate-adjusted analysis, sortilin associated with increased risk of MACCE (hazard ratio, 1.70 per SD; 95% confidence interval, 1.30–2.20; P <0.001). The third and fourth quartiles associated with 3.42-fold (95% confidence interval, 1.61–7.25; P <0.005) and 3.82-fold (95% confidence interval, 1.77–8.26; P 5) after adjustment for confounders (odds ratio, 1.43 per SD; 95% confidence interval, 1.10–1.85; P <0.01). The highest sortilin quartile associated with 2-fold higher odds of severe AAC (versus 3 lower quartiles combined). After adjustment for low-density lipoprotein cholesterol, the odds of severe AAC remained significant. Conclusions— In older men, higher serum sortilin levels associated with higher MACCE risk and severe AAC independently of relevant confounders, including C-reactive protein and low-density lipoprotein cholesterol. This finding, however, needs to be validated in other cohorts.

ACS Style

Claudia Goettsch; Hiroshi Iwata; Joshua D. Hutcheson; Christopher J. O’Donnell; Roland Chapurlat; Nancy R. Cook; Masanori Aikawa; Pawel Szulc; Elena Aikawa. Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men. Arteriosclerosis, Thrombosis, and Vascular Biology 2017, 37, 1005 -1011.

AMA Style

Claudia Goettsch, Hiroshi Iwata, Joshua D. Hutcheson, Christopher J. O’Donnell, Roland Chapurlat, Nancy R. Cook, Masanori Aikawa, Pawel Szulc, Elena Aikawa. Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017; 37 (5):1005-1011.

Chicago/Turabian Style

Claudia Goettsch; Hiroshi Iwata; Joshua D. Hutcheson; Christopher J. O’Donnell; Roland Chapurlat; Nancy R. Cook; Masanori Aikawa; Pawel Szulc; Elena Aikawa. 2017. "Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men." Arteriosclerosis, Thrombosis, and Vascular Biology 37, no. 5: 1005-1011.

Journal article
Published: 31 October 2016 in Nature Communications
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Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9–PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.

ACS Style

Hiroshi Iwata; Claudia Goettsch; Amitabh Sharma; Piero Ricchiuto; Wilson Wen Bin Goh; Arda Halu; Iwao Yamada; Hideo Yoshida; Takuya Hara; Mei Wei; Noriyuki Inoue; Daiju Fukuda; Alexander Mojcher; Peter C. Mattson; Albert Barabasi; Mark Boothby; Elena Aikawa; Sasha A. Singh; Masanori Aikawa. PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nature Communications 2016, 7, 12849 -12849.

AMA Style

Hiroshi Iwata, Claudia Goettsch, Amitabh Sharma, Piero Ricchiuto, Wilson Wen Bin Goh, Arda Halu, Iwao Yamada, Hideo Yoshida, Takuya Hara, Mei Wei, Noriyuki Inoue, Daiju Fukuda, Alexander Mojcher, Peter C. Mattson, Albert Barabasi, Mark Boothby, Elena Aikawa, Sasha A. Singh, Masanori Aikawa. PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nature Communications. 2016; 7 (1):12849-12849.

Chicago/Turabian Style

Hiroshi Iwata; Claudia Goettsch; Amitabh Sharma; Piero Ricchiuto; Wilson Wen Bin Goh; Arda Halu; Iwao Yamada; Hideo Yoshida; Takuya Hara; Mei Wei; Noriyuki Inoue; Daiju Fukuda; Alexander Mojcher; Peter C. Mattson; Albert Barabasi; Mark Boothby; Elena Aikawa; Sasha A. Singh; Masanori Aikawa. 2016. "PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation." Nature Communications 7, no. 1: 12849-12849.

Journal article
Published: 08 September 2016 in Cell Stem Cell
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Summary Mesenchymal stem cell (MSC)-like cells reside in the vascular wall, but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during athero- and arteriosclerosis in ApoE −/− mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.

ACS Style

Rafael Kramann; Claudia Goettsch; Janewit Wongboonsin; Hiroshi Iwata; Rebekka K. Schneider; Christoph Kuppe; Nadine Kaesler; Monica Chang-Panesso; Flavia G. Machado; Susannah Gratwohl; Kaushal Madhurima; Joshua D. Hutcheson; Sanjay Jain; Elena Aikawa; Benjamin D. Humphreys. Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. Cell Stem Cell 2016, 19, 628 -642.

AMA Style

Rafael Kramann, Claudia Goettsch, Janewit Wongboonsin, Hiroshi Iwata, Rebekka K. Schneider, Christoph Kuppe, Nadine Kaesler, Monica Chang-Panesso, Flavia G. Machado, Susannah Gratwohl, Kaushal Madhurima, Joshua D. Hutcheson, Sanjay Jain, Elena Aikawa, Benjamin D. Humphreys. Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. Cell Stem Cell. 2016; 19 (5):628-642.

Chicago/Turabian Style

Rafael Kramann; Claudia Goettsch; Janewit Wongboonsin; Hiroshi Iwata; Rebekka K. Schneider; Christoph Kuppe; Nadine Kaesler; Monica Chang-Panesso; Flavia G. Machado; Susannah Gratwohl; Kaushal Madhurima; Joshua D. Hutcheson; Sanjay Jain; Elena Aikawa; Benjamin D. Humphreys. 2016. "Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease." Cell Stem Cell 19, no. 5: 628-642.

Journal article
Published: 09 June 2016 in Atherosclerosis
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Background and aims Studying atherosclerotic calcification in vivo requires mouse models with genetic modifications. Previous studies showed that injection of recombinant adeno-associated virus vector (AAV) encoding a gain-of-function mutant PCSK9 into mice promotes atherosclerosis. We aimed to study cardiovascular calcification induced by PCSK9 AAV in C57BL/6J mice. Methods 10 week-old C57BL/6J mice received a single injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9). Ldlr –/– mice served as positive controls. Mice consumed a high-fat, high-cholesterol diet for 15 or 20 weeks. Aortic calcification was assessed by fluorescence reflectance imaging (FRI) of a near-infrared calcium tracer. Results Serum levels of PCSK9 (0.14 μg/mL to 20 μg/mL, p < 0.01) and total cholesterol (82 mg/dL to 820 mg/dL, p < 0.01) increased within one week after injection and remained elevated for 20 weeks. Atherosclerotic lesion size was similar between PCSK9 AAV and Ldlr –/– mice. Aortic calcification was 0.01% ± 0.01 in PCSK9 AAV mice and 15.3% ± 6.1 in Ldlr –/– mice at 15 weeks (p < 0.01); by 20 weeks, the PCSK9 AAV mice aortic calcification grew to 12.4% ± 4.9. Tissue non-specific alkaline phosphatase activity was similar in PCSK9 AAV mice and Ldlr –/– mice at 15 and 20 weeks, respectively. As example of the utility of this model in testing modulators of calcification in vivo, PCSK9 AAV injection to sortilin-deficient mice demonstrated reduced aortic calcification by 46.3% (p < 0.05) compared to littermate controls. Conclusions A single injection of gain-of-function PCSK9 AAV into C57BL/6J mice is a useful tool to study cardiovascular calcification in mice with no genetic manipulation.

ACS Style

Claudia Goettsch; Joshua D. Hutcheson; Sumihiko Hagita; Maximillian Rogers; Michael D. Creager; Tan Pham; Jung Choi; Andrew K. Mlynarchik; Brett Pieper; Mads Kjolby; Masanori Aikawa; Elena Aikawa. A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification. Atherosclerosis 2016, 251, 109 -118.

AMA Style

Claudia Goettsch, Joshua D. Hutcheson, Sumihiko Hagita, Maximillian Rogers, Michael D. Creager, Tan Pham, Jung Choi, Andrew K. Mlynarchik, Brett Pieper, Mads Kjolby, Masanori Aikawa, Elena Aikawa. A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification. Atherosclerosis. 2016; 251 ():109-118.

Chicago/Turabian Style

Claudia Goettsch; Joshua D. Hutcheson; Sumihiko Hagita; Maximillian Rogers; Michael D. Creager; Tan Pham; Jung Choi; Andrew K. Mlynarchik; Brett Pieper; Mads Kjolby; Masanori Aikawa; Elena Aikawa. 2016. "A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification." Atherosclerosis 251, no. : 109-118.

Journal article
Published: 17 March 2016 in Journal of Molecular and Cellular Cardiology
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Purpose Calcific aortic valve disease (CAVD) is the most prevalent valve disease in the Western world. Recent difficulty in translating experimental results on statins to beneficial clinical effects warrants the need for understanding the role of valvular interstitial cells (VICs) in CAVD. In two-dimensional culture conditions, VICs undergo spontaneous activation similar to pathological differentiation, which intrinsically limits the use of in vitro models to study CAVD. Here, we hypothesized that a three-dimensional (3D) culture system based on naturally derived extracellular matrix polymers, mimicking the microenvironment of native valve tissue, could serve as a physiologically relevant platform to study the osteogenic differentiation of VICs. Principal results Aortic VICs loaded into 3D hydrogel constructs maintained a quiescent phenotype, similar to healthy human valves. In contrast, osteogenic environment induced an initial myofibroblast differentiation (hallmarked by increased alpha smooth muscle actin [α-SMA] expression), followed by an osteoblastic differentiation, characterized by elevated Runx2 expression, and subsequent calcific nodule formation recapitulating CAVD conditions. Silencing of α-SMA under osteogenic conditions diminished VIC osteoblast-like differentiation and calcification, indicating that a VIC myofibroblast-like phenotype may precede osteogenic differentiation in CAVD. Major conclusions Using a 3D hydrogel model, we simulated events that occur during early CAVD in vivo and provided a platform to investigate mechanisms of CAVD. Differentiation of valvular interstitial cells to myofibroblasts was a key mechanistic step in the process of early mineralization. This novel approach can provide important insight into valve pathobiology and serve as a promising tool for drug screening.

ACS Style

Jesper Hjortnaes; Claudia Goettsch; Joshua D. Hutcheson; Gulden Camci-Unal; Lilian Lax; Katrin Scherer; Simon Body; Frederick J. Schoen; Jolanda Kluin; Ali Khademhosseini; Elena Aikawa. Simulation of early calcific aortic valve disease in a 3D platform: A role for myofibroblast differentiation. Journal of Molecular and Cellular Cardiology 2016, 94, 13 -20.

AMA Style

Jesper Hjortnaes, Claudia Goettsch, Joshua D. Hutcheson, Gulden Camci-Unal, Lilian Lax, Katrin Scherer, Simon Body, Frederick J. Schoen, Jolanda Kluin, Ali Khademhosseini, Elena Aikawa. Simulation of early calcific aortic valve disease in a 3D platform: A role for myofibroblast differentiation. Journal of Molecular and Cellular Cardiology. 2016; 94 ():13-20.

Chicago/Turabian Style

Jesper Hjortnaes; Claudia Goettsch; Joshua D. Hutcheson; Gulden Camci-Unal; Lilian Lax; Katrin Scherer; Simon Body; Frederick J. Schoen; Jolanda Kluin; Ali Khademhosseini; Elena Aikawa. 2016. "Simulation of early calcific aortic valve disease in a 3D platform: A role for myofibroblast differentiation." Journal of Molecular and Cellular Cardiology 94, no. : 13-20.

Journal article
Published: 07 March 2016 in Journal of Clinical Investigation
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Vascular calcification is a common feature of major cardiovascular diseases. Extracellular vesicles participate in the formation of microcalcifications that are implicated in atherosclerotic plaque rupture; however, the mechanisms that regulate formation of calcifying extracellular vesicles remain obscure. Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC) calcification via its recruitment to extracellular vesicles. Sortilin localized to calcifying vessels in human and mouse atheromata and participated in formation of microcalcifications in SMC culture. Sortilin regulated the loading of the calcification protein tissue nonspecific alkaline phosphatase (TNAP) into extracellular vesicles, thereby conferring its calcification potential. Furthermore, SMC calcification required Rab11-dependent trafficking and FAM20C/casein kinase 2–dependent C-terminal phosphorylation of sortilin. In a murine model, Sort1-deficiency reduced arterial calcification but did not affect bone mineralization. Additionally, transfer of sortilin-deficient BM cells to irradiated atherosclerotic mice did not affect vascular calcification, indicating a primary role of SMC-derived sortilin. Together, the results of this study identify sortilin phosphorylation as a potential therapeutic target for ectopic calcification/microcalcification and may clarify the mechanism that underlies the genetic association between the SORT1 gene locus and coronary artery calcification.

ACS Style

Claudia Goettsch; Joshua D. Hutcheson; Masanori Aikawa; Hiroshi Iwata; Tan Pham; Anders Nykjaer; Mads Kjolby; Maximillian Rogers; Thomas Michel; Manabu Shibasaki; Sumihiko Hagita; Rafael Johannes Thomas Kramann; Daniel J. Rader; Peter Libby; Sasha A. Singh; Elena Aikawa. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. Journal of Clinical Investigation 2016, 126, 1323 -1336.

AMA Style

Claudia Goettsch, Joshua D. Hutcheson, Masanori Aikawa, Hiroshi Iwata, Tan Pham, Anders Nykjaer, Mads Kjolby, Maximillian Rogers, Thomas Michel, Manabu Shibasaki, Sumihiko Hagita, Rafael Johannes Thomas Kramann, Daniel J. Rader, Peter Libby, Sasha A. Singh, Elena Aikawa. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. Journal of Clinical Investigation. 2016; 126 (4):1323-1336.

Chicago/Turabian Style

Claudia Goettsch; Joshua D. Hutcheson; Masanori Aikawa; Hiroshi Iwata; Tan Pham; Anders Nykjaer; Mads Kjolby; Maximillian Rogers; Thomas Michel; Manabu Shibasaki; Sumihiko Hagita; Rafael Johannes Thomas Kramann; Daniel J. Rader; Peter Libby; Sasha A. Singh; Elena Aikawa. 2016. "Sortilin mediates vascular calcification via its recruitment into extracellular vesicles." Journal of Clinical Investigation 126, no. 4: 1323-1336.

Journal article
Published: 11 January 2016 in Nature Materials
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Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification areas. We also show that calcification morphology and the plaque’s collagen content—two determinants of atherosclerotic plaque stability—are interlinked. The formation of atherosclerotic plaques involves the aggregation of calcifying extracellular vesicles and the formation of microcalcifications.

ACS Style

Joshua D. Hutcheson; Claudia Goettsch; Sergio Bertazzo; Natalia Maldonado; Jessica L. Ruiz; Wilson Wen Bin Goh; Katsumi Yabusaki; Tyler Faits; Carlijn Bouten; Grégory Franck; Thibaut Quillard; Peter Libby; Masanori Aikawa; Sheldon Weinbaum; Elena Aikawa. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nature Materials 2016, 15, 335 -343.

AMA Style

Joshua D. Hutcheson, Claudia Goettsch, Sergio Bertazzo, Natalia Maldonado, Jessica L. Ruiz, Wilson Wen Bin Goh, Katsumi Yabusaki, Tyler Faits, Carlijn Bouten, Grégory Franck, Thibaut Quillard, Peter Libby, Masanori Aikawa, Sheldon Weinbaum, Elena Aikawa. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nature Materials. 2016; 15 (3):335-343.

Chicago/Turabian Style

Joshua D. Hutcheson; Claudia Goettsch; Sergio Bertazzo; Natalia Maldonado; Jessica L. Ruiz; Wilson Wen Bin Goh; Katsumi Yabusaki; Tyler Faits; Carlijn Bouten; Grégory Franck; Thibaut Quillard; Peter Libby; Masanori Aikawa; Sheldon Weinbaum; Elena Aikawa. 2016. "Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques." Nature Materials 15, no. 3: 335-343.

Review
Published: 01 October 2015 in Seminars in Cell & Developmental Biology
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The presence of cardiovascular calcification significantly predicts patients' morbidity and mortality. Calcific mineral deposition within the soft cardiovascular tissues disrupts the normal biomechanical function of these tissues, leading to complications such as heart failure, myocardial infarction, and stroke. The realization that calcification results from active cellular processes offers hope that therapeutic intervention may prevent or reverse the disease. To this point, however, no clinically viable therapies have emerged. This may be due to the lack of certainty that remains in the mechanisms by which mineral is deposited in cardiovascular tissues. Gaining new insight into this process requires a multidisciplinary approach. The pathological changes in cell phenotype that lead to the physicochemical deposition of mineral and the resultant effects on tissue biomechanics must all be considered when designing strategies to treat cardiovascular calcification. In this review, we overview the current cardiovascular calcification paradigm and discuss emerging techniques that are providing new insight into the mechanisms of ectopic calcification.

ACS Style

Joshua D. Hutcheson; Claudia Goettsch; Maximillian A. Rogers; Elena Aikawa. Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach. Seminars in Cell & Developmental Biology 2015, 46, 68 -77.

AMA Style

Joshua D. Hutcheson, Claudia Goettsch, Maximillian A. Rogers, Elena Aikawa. Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach. Seminars in Cell & Developmental Biology. 2015; 46 ():68-77.

Chicago/Turabian Style

Joshua D. Hutcheson; Claudia Goettsch; Maximillian A. Rogers; Elena Aikawa. 2015. "Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach." Seminars in Cell & Developmental Biology 46, no. : 68-77.