Deficiency of lncRNA SNHG12 impairs DNA damage repair in the vessel wall and predisposes to vascular senescence and atherosclerosis.

Purpose of review Long noncoding RNAs (lncRNAs) have emerged as powerful regulators of nearly all biological processes. Their cell-type and tissue-specific expression in health and disease provides new avenues for diagnosis and therapy. This review highlights the role of lncRNAs that are involved in cardiovascular disease (CVD) with a special focus on cell types involved in cardiac injury and remodeling, vascular injury, angiogenesis, inflammation, and lipid metabolism. Recent findings Almost 98% of the genome does not encode for proteins. LncRNAs are among the most abundant type of RNA in the noncoding genome. Accumulating studies have uncovered novel lncRNA-mediated regulation of CVD-associated genes, signaling pathways, and pathophysiological responses. Targeting lncRNAs in vivo using short antisense oligonucleotides or by gene editing has provided important insights into disease pathogenesis through epigenetic, transcriptional, or translational mechanisms. Although cross-species conservation still remains a major obstacle, there is increasing appreciation that altered expression of lncRNAs associates with stage-specific CVD and in human patient cohorts, providing new opportunities for diagnosis and therapy. Summary A better understanding of lncRNAs will not only fundamentally improve our understanding of key signaling pathways in CVD, but also aid in the development of effective new therapies and RNA-based biomarkers.

Thrombogenic and inflammatory mediators, such as thrombin, induce NF‐kB–mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti‐inflammatory microRNA‐181b (miR‐181b) on thrombosis remains unknown. Our previous study demonstrated that miR‐181b inhibits downstream NF‐kB signaling in response to TNF‐a. Here, we demonstrate that miR‐181b uniquely inhibits upstream NF‐kB signaling in response to thrombin. Overexpression of miR‐181b inhibited thrombin‐induced activation of NF‐kB signaling, demonstratedbyreductionofphospho‐IKK‐b,‐IkB‐a, and p65 nuclear translocation in ECs. MiR‐181b also reduced expression of NF‐kB target genes VCAM‐1, intercellular adhesion molecule‐1, E‐selectin, and tissue factor. Mechanistically, miR‐181b targets caspase recruitment domain family member 10 (Card10), an adaptor protein that participates in activation of the IKK complex in response to signals transduced from protease‐activated receptor‐1. miR‐181b reduced expression of Card10 mRNA and protein, but not protease‐activated receptor‐1. 39‐Untranslated region reporter assays, argonaute‐2 microribonucleoprotein immunoprecipitation studies, and Card10 rescue studies revealed that Card10 is a bona fide direct miR‐181b target. Small interfering RNA–mediated knockdown of Card10 expression phenocopied effects of miR‐181b on NF‐kB signaling and targets. Card10 deficiency did not affect TNF‐a–induced activation of NF‐kB signaling, which suggested stimulus‐specific regulation of NF‐kB signaling and endothelial responses by miR‐181b in ECs. Finally, in response to photochemical injury‐induced arterial thrombosis, systemic delivery of miR‐181b reduced thrombus formation by 73% in carotid arteries and prolonged time to occlusion by 1.6‐fold, effects recapitulated by Card10 small interfering RNA. These data demonstrate that miR‐181b and Card10 are important regulators of thrombin‐induced EC activation and arterial thrombosis. These studies highlight the relevance of microRNA‐dependent targets in response to ligand‐specific signaling in ECs.—Lin, J., He, S., Sun, X., Franck, G., Deng, Y., Yang, D., Haemmig, S., Wara, A. K. M., Icli, B., Li, D., Feinberg, M. W. MicroRNA‐181b inhibits thrombin‐mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10. FASEB J. 30, 3216–3226 (2016). www.fasebj.org

Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from Ampelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4‐positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E‐deficient (Apoe^−/−) mice. Yet, those protective effects are abrogated by using NOS inhibitor L‐NAME in Apoe^−/− mice received DMY. Mechanistically, DMY decreases microRNA‐21 (miR‐21) and increases its target gene dimethylarginine dimethylaminohydrolase‐1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR‐21 in Apoe^−/− mice or miR‐21 overexpression in cultured HUVECs abrogates those DMY‐mediated protective effects. These data demonstrate that endothelial miR‐21‐inhibited DDAH1‐ADMA‐eNOS‐NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.

A prominent phenotype of IRF8 knockout (KO) mice is the uncontrolled expansion of immature myeloid cells. The molecular mechanism underlying this myeloproliferative syndrome is still elusive. In this study, we observed that Bax expression level is low in bone marrow preginitor cells and increases dramatically in primary myeloid cells in wt mice. In contrast, Bax expression level remained at a low level in primarymyeloid cells in IRF8 KO mice. However, in vitro IRF8 KO bone marrow-differentiated myeloid cells expressed Bax at a level as high as that in wild type myeloid cells. Furthermore, we demonstrated that IRF8 specifically binds to the Bax promoter region in primary myeloid cells. Functional analysis indicated that IRF8 deficiency results in increased resistance of the primary myeloid cells to Fas-mediated apoptosis. Our findings show that IRF8 directly regulates Bax transcription in vivo, but not in vitro during myeloid cell lineage differentiation.

Cardiomyocytes hypertrophy and apoptosis induced by advanced glycation end products (AGEs) is the crucial pathological foundation contributing to the onset and development of diabetic cardiomyopathy (DCM). However, the mechanism remains poorly understood. Here, we report that profilin-1 (PFN-1), a well-known actin-binding protein, serves as a potent regulator in AGEs-induced cardiomyocytes hypertrophy and apoptosis. PFN-1 was upregulated in AGEs-treated H9c2 cells, which was associated with increased cardiomyocytes hypertrophy and apoptosis. Silencing PFN-1 expression remarkably attenuated AGEs-induced H9c2 cell hypertrophy and apoptosis. Mechanistically, AGEs increased PFN-1 expression through elevating ROS production and RhoA and ROCK2 expression. Consequently, elevated PFN-1 promoted actin cytoskeleton disorganization. When either ROS production/ROCK activation was blocked or cells were treated with Cytochalasin D (actin depolymerizer), H9c2 cells were protected against AGEs-induced cardiac myocyte abnormalities, concomitantly with downregulated expression of PFN-1 and improved actin cytoskeleton alteration. Collectively, these data suggest that PFN-1 may play an important role in AGEs-induced hypertrophy and apoptosis in H9c2 cells.