Circular RNAs are generated from many protein-coding genes, but their role in cardiovascular health and disease states remains unknown. Here we report identification of circRNA transcripts that are differentially expressed in post myocardial infarction (MI) mouse hearts including circFndc3b which is significantly down-regulated in the post-MI hearts. Notably, the human circFndc3b ortholog is also significantly down-regulated in cardiac tissues of ischemic cardiomyopathy patients. Overexpression of circFndc3b in cardiac endothelial cells increases vascular endothelial growth factor-A expression and enhances their angiogenic activity and reduces cardiomyocytes and endothelial cell apoptosis. Adeno-associated virus 9 -mediated cardiac overexpression of circFndc3b in post-MI hearts reduces cardiomyocyte apoptosis, enhances neovascularization and improves left ventricular functions. Mechanistically, circFndc3b interacts with the RNA binding protein Fused in Sarcoma to regulate VEGF expression and signaling. These findings highlight a physiological role for circRNAs in cardiac repair and indicate that modulation of circFndc3b expression may represent a potential strategy to promote cardiac function and remodeling after MI.

Endothelial dysfunction is a pathological status of the vascular system, which can be broadly defined as an imbalance between endothelium-dependent vasoconstriction and vasodilation. Endothelial dysfunction is a key event in the progression of many pathological processes including atherosclerosis, type II diabetes and hypertension. Previous reports have demonstrated that pro-inflammatory/immunoeffector cytokines significantly promote endothelial dysfunction while numerous novel anti-inflammatory/immunosuppressive cytokines have recently been identified such as interleukin (IL)-35. However, the effects of anti-inflammatory cytokines on endothelial dysfunction have received much less attention. In this analytical review, we focus on the recent progress attained in characterizing the direct and indirect effects of anti-inflammatory/immunosuppressive cytokines in the inhibition of endothelial dysfunction. Our analyses are not only limited to the importance of endothelial dysfunction in cardiovascular disease progression, but also expand into the molecular mechanisms and pathways underlying the inhibition of endothelial dysfunction by anti-inflammatory/immunosuppressive cytokines. Our review suggests that anti-inflammatory/immunosuppressive cytokines serve as novel therapeutic targets for inhibiting endothelial dysfunction, vascular inflammation and cardio- and cerebro-vascular diseases.

Endothelial dysfunction is associated with hypertension, hypercholesterolemia, and heart failure. We tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK) rats, a model for type 2 diabetes, exhibit endothelial dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt]) and chronic angiotensin type 1 (AT ₁ ) receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with age-matched nondiabetic Wistar control rats, GK rats had higher blood glucose levels (9.3±0.5 versus 6.9±0.2 mmol/L for control rats), 2.7-fold higher serum insulin levels, and impaired glucose tolerance (all P <0.05). Telemetry-measured mean blood pressure was 15 mm Hg higher in GK rats ( P <0.01) compared with control rats, whereas heart rates were not different. Heart weight– and kidney weight–to–body weight ratios were higher in GK rats ( P <0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesenteric arterial rings by acetylcholine was impaired compared with the control condition ( P <0.05), whereas the sodium nitroprusside–induced relaxation was similar. Preincubation of the arterial rings with the NO synthase inhibitor N ^G -nitro- l -arginine methyl ester and the cyclooxygenase inhibitor diclofenac inhibited relaxations to acetylcholine almost completely in GK rats but not in Wistar rats, suggesting that endothelial dysfunction can be in part attributed to reduced relaxation via arterial K ⁺ channels. Perivascular monocyte/macrophage infiltration and intercellular adhesion molecule-1 overexpression were observed in GK rat kidneys. A high-sodium diet increased blood pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hypertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation (all P <0.05). The serum level of 8-isoprostaglandin F _2α , a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased 400% in GK rats on a high-sodium diet. Valsartan decreased blood pressure in rats fed a low-sodium diet and prevented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but protected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT ₁ receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT ₁ receptor expression, medullary and cortical angiotensin type 2 (AT ₂ ) receptor expressions, and adrenal ACE and neutral endopeptidase expressions were unchanged. A high-sodium diet did not influence renal AT ₁ , AT ₂ , ACE, or neutral endopeptidase expressions. In valsartan-treated GK rats, the cortical and medullary AT ₁ receptor expressions were decreased in the presence and absence of a high-sodium diet. A high-sodium diet increased plasma brain natriuretic peptide concentrations in presence and absence of valsartan treatment. We conclude that hypertension in GK rats is salt sensitive and associated with endothelial dysfunction and perivascular inflammation. AT ₁ receptor blockade ameliorates inflammation during a low-sodium diet and partially protects against salt-induced vascular damage by blood pressure–independent mechanisms.

Background: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload–induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload–induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC–mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload–induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. Methods: Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. Results: Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow–depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction–induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with α-smooth muscle actin or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction–induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-β–induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction–based selective miRNA analysis revealed that transforming growth factor-β–induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-β–induced fibrotic signaling in BM-FPCs. Conclusions: Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad–miRNA-21–mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

Diabetes is one of the most prevalent metabolic disorders and is estimated to affect 400 million of 4.4% of population worldwide in the next 20 year. In diabetes, risk to develop vascular diseases is two-to four-fold increased. Ischemic tissue injury, such as refractory wounds and critical ischemic limb (CLI) are major ischemic vascular complications in diabetic patients where oxygen supplement is insufficient due to impaired angiogenesis/neovascularization. In spite of intensive studies, the underlying mechanisms of diabetes-impaired ischemic tissue injury remain incompletely understood. Hydrogen sulfide (H2S) has been considered as a third gasotransmitter regulating angiogenesis under physiological and ischemic conditions. Here, the underlying mechanisms of insufficient H2S-impaired angiogenesis and ischemic tissue repair in diabetes are discussed. We will primarily focuses on the signaling pathways of H2S in controlling endothelial function/biology, angiogenesis and ischemic tissue repair in diabetic animal models. We summarized that H2S plays an important role in maintaining endothelial function/biology and angiogenic property in diabetes. We demonstrated that exogenous H2S may be a theraputic agent for endothelial dysfunction and impaired ischemic tissue repair in diabetes.