BDNF-mediates Down-regulation of MicroRNA-195 Inhibits Ischemic Cardiac Apoptosis in Rats

Abstract

Background: Our previous studies suggested that brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) axis inhibited cardiomyocyte apoptosis in myocardial infarction (MI). However, the relationship between BDNF and microRNA (miRNA) in cardiomyocytes are unclear. The present study was performed to investigate the role of miR-195 and the interplay between BDNF and miR-195 in ischemic cardiomyocyte apoptosis.Methods: Male Wistar rats were subjected to coronary artery ligation, and primary neonatal rat ventricular myocytes were treated with hypoxia or hydrogen peroxide (H2O2). BDNF level in rat ventricles was measured by enzyme linked immunosorbent assay (ELISA). miR-195 mimic, inhibitor or negative control was transfected into the cardiomyocytes. Cell viability and apoptosis were detected by MTT assay and TdT-mediated dUTP nick end labeling (TUNEL) staining, respectively. Cardiac function and apoptosis were detected in MI rats intravenously injected with antagomiR-195. Luciferase assay, Western blot and Real-time RT-PCR were employed to clarify the interplay between miR-195 and BDNF.Results: miR-195 level was dynamically regulated in response to MI and significantly increased in ischemic regions 24 h post-MI as well as in hypoxic or H2O2-treated cardiomyocytes. Meanwhile, BDNF protein level was rapidly increased in MI rats and H2O2-treated cardiomyocytes. Apoptosis in both hypoxic and H2O2-treated cardiomyocytes were markedly reduced and cell viability was increased by miR-195 inhibitor. Moreover, inhibition of miR-195 significantly improved cardiac function of MI rats. Bcl-2 but not BDNF was validated as the direct target of miR-195. Furthermore, BDNF abolished the pro-apoptotic role of miR-195, which was reversed by its scavenger TrkB-Fc.Conclusion: Up-regulation of miR-195 in ischemic cardiomyocytes promotes ischemic apoptosis by targeting Bcl-2. BDNF mitigated the pro-apoptotic effect of miR-195 in rat cardiomyocytes. These findings may provide better understanding of the pro-apoptotic role of miR-195 in MI and suggest that BDNF/miR-195/Bcl-2 axis may be beneficial for limiting myocardial ischemic injury.

Brain‐Derived Neurotrophic Factor Attenuates Septic Myocardial Dysfunction via eNOS/NO Pathway in Rats

“…Given that apoptosis and the subsequent cell loss, which were stimulated by oxidative stress, have been considered a driving force and the major mechanism in sepsis-induced myocardial dysfunction [37], the observed cardioprotective effects of BDNF in the hearts from septic shock rats may act through reducing oxidative stress and the subsequent reduction of cardiomyocytes apoptosis. Our findings were similar to the study by Hang et al which showed that BDNF by downregulating microRNA-195 inhibited cardiac apoptosis and attenuated myocardial ischemia reperfusion injury in rats [38]. In the current study, we further demonstrated that the abovementioned beneficial effects of BDNF were mainly through NOS system.…”

Resveratrol Improves Cognitive Impairment by Regulating Apoptosis and Synaptic Plasticity in Streptozotocin-Induced Diabetic Rats

“…Recent studies indicate that BDNF plays an important role in the regulation of hippocampal synaptic plasticity [24]. BDNF has also been reported to be an important regulator of neuronal apoptosis [25,26]. In the present study, we found that after diabetic modeling, BDNF expression was decreased, while resveratrol treatment reversed the down-regulation.…”

Mitochondrial MiRNA in Cardiovascular Function and Disease

“…Other nuclear-encoded miRNAs have been found to directly regulate mitochondrial proteins in the ischemic heart. For example, the upregulation of miR-15/16 family and miR-195 suppressed ATP levels and induced mitochondrial fusion, by acting on their common target ADP-ribosylation factor-like 2 to influence cardiomyocyte survival and contribute to myocardial infarction [61][62][63]. Inhibition of miR-15 family protected against ischemia/reperfusion heart injury in vivo through directly de-repression of pyruvate dehydrogenase kinase 4 and serum/glucocorticoid-regulated kinase 1, which regulate mitochondrial function and apoptosis, respectively [61].…”