With the onset of advanced age, cardiac‐associated pathologies have increased in prevalence. The hallmarks of cardiac aging include cardiomyocyte senescence, fibroblast proliferation, inflammation, and hypertrophy. The imbalance between levels of reactive oxygen species (ROS) and antioxidant enzymes is greatly enhanced in aging cells, promoting cardiac remodeling. In this work, we studied the long‐term impact of phenolic compounds (PC) on age‐associated cardiac remodeling. Three‐month‐old Wistar rats were treated for 14 months till middle‐age with either 2.5, 5, 10, or 20 mg kg⁻¹ day⁻¹ of PC. PC treatment showed a dose‐dependent preservation of cardiac ejection fraction and fractional shortening as well as decreased hypertrophy reflected by left ventricular chamber diameter and posterior wall thickness as compared to untreated middle‐aged control animals. Analyses of proteins from cardiac tissue showed that PC attenuated several hypertrophic pathways including calcineurin/nuclear factor of activated T cells (NFATc3), calcium/calmodulin‐dependent kinase II (CAMKII), extracellular regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase 3ß (GSK 3ß). PC‐treated groups exhibited reduced plasma inflammatory and fibrotic markers and revealed as well ameliorated extracellular matrix remodeling and interstitial inflammation by a downregulated p38 pathway. Myocardia from PC‐treated middle‐aged rats presented less fibrosis with suppression of profibrotic transforming growth factor‐ß1 (TGF‐ß1) Smad pathway. Additionally, reduction of apoptosis and oxidative damage in the PC‐treated groups was reflected by elevated antioxidant enzymes and reduced RNA/DNA damage markers. Our findings pinpoint that a daily consumption of phenolic compounds could preserve the heart from the detrimental effects of aging storm.

Diabetes mellitus is a metabolic disorder denoted by chronic hyperglycemia that drives maladaptive structural changes and functional damage to the vasculature. Attenuation of this pathological remodeling of blood vessels remains an unmet target owing to paucity of information on the metabolic signatures of this process. Ca²⁺/calmodulin-dependent kinase II (CaMKII) is expressed in the vasculature and is implicated in the control of blood vessels homeostasis. Recently, CaMKII has attracted a special attention in view of its chronic upregulated activity in diabetic tissues, yet its role in the diabetic vasculature remains under investigation.This review highlights the physiological and pathological actions of CaMKII in the diabetic vasculature, with focus on the control of the dialogue between endothelial (EC) and vascular smooth muscle cells (VSMC). Activation of CaMKII enhances EC and VSMC proliferation and migration, and increases the production of extracellular matrix which leads to maladaptive remodeling of vessels. This is manifested by activation of genes/proteins implicated in the control of the cell cycle, cytoskeleton organization, proliferation, migration, and inflammation. Endothelial dysfunction is paralleled by impaired nitric oxide signaling, which is also influenced by CaMKII signaling (activation/oxidation). The efficiency of CaMKII inhibitors is currently being tested in animal models, with a focus on the genetic pathways involved in the regulation of CaMKII expression (microRNAs and single nucleotide polymorphisms). Interestingly, studies highlight an interaction between the anti-diabetic drugs and CaMKII expression/activity which requires further investigation. Together, the studies reviewed herein may guide pharmacological approaches to improve health-related outcomes in patients with diabetes.

Aims: Cardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activated T cells c3 (NFATc3) signaling in rodent and human ventricular CFs, and whether their modulation would limit MF. Results: A positive feedback loop between TRPC3 and NFATc3 drove a rat ventricular CF fibrotic phenotype. In these cells, polyphenols (extract of grape pomace polyphenol [P.E.]) decreased basal and angiotensin II-mediated Ca ²⁺ entries through a direct modulation of TRPC3 channels and subsequently NFATc3 signaling, abrogating myofibroblast differentiation, fibrosis and inflammation, as well as an oxidative stress-associated phenotype. N(ω)-nitro- l -arginine methyl ester ( l -NAME) hypertensive rats developed coronary perivascular, sub-epicardial, and interstitial fibrosis with induction of embryonic epicardial progenitor transcription factors in activated CFs. P.E. treatment reduced ventricular CF activation by modulating the TRPC3-NFATc3 pathway, and it ameliorated echocardiographic parameters, cardiac stress markers, and MF in l -NAME hypertensive rats independently of blood pressure regulation. Further, genetic deletion (TRPC3 ^−/− ) and pharmacological channel blockade with N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-benzenesulfonamide (Pyr10) blunted ventricular CF activation and MF in l -NAME hypertensive mice. Finally, TRPC3 was present in human ventricular CFs and upregulated in MF, whereas pharmacological modulation of TRPC3-NFATc3 decreased proliferation and collagen secretion. Innovation and Conclusion: We demonstrate that TRPC3-NFATc3 signaling is modulated by P.E. and critically regulates ventricular CF phenotype and MF. These findings strongly argue for P.E., through TRPC3 targeting, as potential and interesting therapeutics for MF management.