Brain-Derived Neurotrophic Factor Regulates TRPC3/6 Channels and Protects Against Myocardial Infarction in Rodents

Abstract

Background: Brain-derived neurotrophic factor (BDNF) is associated with coronary artery diseases. However, its role and mechanism in myocardial infarction (MI) is not fully understood.Methods: Wistar rat and Kunming mouse model of MI were induced by the ligation of left coronary artery. Blood samples were collected from MI rats and patients. Plasma BDNF level, protein expression of BDNF, tropomyosin-related kinase B (TrkB) and its downstream transient receptor potential canonical (TRPC)3/6 channels were examined by enzyme-linked immunosorbent assay and Western blot. Infarct size, cardiac function and cardiomyocyte apoptosis were measured after intra-myocardium injection with recombinant human BDNF. Protective role of BDNF against cardiomyocyte apoptosis was confirmed by BDNF scavenger TrkB-Fc. The regulation of TRPC3/6 channels by BDNF was validated by pretreating with TRPC blocker (2-Aminoethyl diphenylborinate, 2-APB) and TRPC3/6 siRNAs.Results: Circulating BDNF was significantly enhanced in MI rats and patients. Protein expression of BDNF, TrkB and TRPC3/6 channels were upregulated in MI. 3 days post-MI, BDNF treatment markedly reduced the infarct size and serum lactate dehydrogenase activity. Meanwhile, echocardiography indicated that BDNF significantly improved cardiac function of MI mice. Furthermore, BDNF markedly inhibited cardiomyocyte apoptosis by upregulating Bcl-2 expression and downregulating caspase-3 expression and activity in ischemic myocardium. In neonatal rat ventricular myocytes, cell viability was dramatically increased by BDNF in hypoxia, which was restored by TrkB-Fc. Furthermore, protective role of BDNF against hypoxia-induced apoptosis was reversed by 2-APB and TRPC3/6 siRNAs.Conclusion: BDNF/TrkB alleviated cardiac ischemic injury and inhibited cardiomyocytes apoptosis by regulating TRPC3/6 channels, which provides a novel potential therapeutic candidate for MI.

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

“…Total protein was extracted from ischemic border zone of rat left ventricles for western blotting analysis as described previously [24]. SDS-PAGE was conducted to separate protein and further detect corresponding protein expression.…”

Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts

“…BDNF has been well-characterized as a growth and pro-survival factor in a variety of cell types, including neurons [38], skeletal muscle stem cells, [39] and more recently cardiac progenitor cells [40]. BDNF also promotes angiogenesis, improves left ventricular function under ischemic conditions [41,42] and protects against adverse cardiac remodeling after myocardial infarction [43,44]. Plasma levels of BDNF were found to be significantly decreased in patients with heart failure, and circulating levels of BDNF levels were associated with cardiac disease severity [45].…”

“TRP inflammation” relationship in cardiovascular system

“…After BDNF treatment, the infarct size was markedly reduced and cardiac contractility was significantly restored, which seemed to be associated with decreased apoptotic response of cardiomyocytes. Since these beneficial effects of BDNF were reversed by pharmacological or functional inhibition of TRPC3/TRPC6 channels, these channels likely play a protective role against detrimental cardiac remodeling after MI [132,174]. In a puzzling contrast, however, adenovirus-mediated overexpression of TRPC3/TRPC4/TRPC6 was reported to induce a hypertrophic response via the NFAT-mediated signaling in adult feline cardiomyocytes and accompany reduction of the contractility and catecholamine response due to increased spontaneous Ca 2+ leak from the SR.…”