Abstract
Adiponectin and miR-133a are key regulators in cardiac hypertrophy. However, whether APN has a potential effect on miR-133a remains unclear. In this study, we aimed to investigate whether APN could regulate miR-133a expression in Angiotensin II (Ang II) induced cardiac hypertrophy in vivo and in vitro. Lentiviral-mediated adiponectin treatment attenuated cardiac hypertrophy induced by Ang II infusion in male wistar rats as determined by reduced cell surface area and mRNA levels of atrial natriuretic peptide (ANF) and brain natriuretic peptide (BNP), also the reduced left ventricular end-diastolic posterior wall thickness (LVPWd) and end-diastolic interventricular septal thickness (IVSd). Meanwhile, APN elevated miR-133a level which was downregulated by Ang II. To further investigate the underlying molecular mechanisms, we treated neonatal rat ventricular myocytes (NRVMs) with recombinant rat APN before Ang II stimulation. Pretreating cells with recombinant APN promoted AMP-activated protein kinase (AMPK) phosphorylation and inhibited ERK activation. By using the inhibitor of AMPK or a lentiviral vector expressing AMPK short hairpin RNA (shRNA) cancelled the positive effect of APN on miR-133a. The ERK inhibitor PD98059 reversed the downregulation of miR-133a induced by Ang II. These results indicated that the AMPK activation and ERK inhibition were responsible for the positive effect of APN on miR-133a. Furthermore, adiponectin receptor 1 (AdipoR1) mRNA expression was inhibited by Ang II stimulation. The positive effects of APN on AMPK activation and miR-133a, and the inhibitory effect on ERK phosphorylation were inhibited in NRVMs transfected with lentiviral AdipoR1shRNA. In addition, APN depressed the elevated expression of connective tissue growth factor (CTGF), a direct target of miR-133a, through the AMPK pathway. Taken together, our data indicated that APN reversed miR-133a levels through AMPK activation, reduced ERK1/2 phosphorylation in cardiomyocytes stimulated with Ang II, revealing a previously undemonstrated and important link between APN and miR-133a.
Highlights
Cardiomyocyte hypertrophy is a maladaptive response to cardiac insults, such as hypertension, myocardial infarction, valvular heart disease, cardiomyopathy, and congenital heart disease
The results showed that Angiotensin II (Ang II) infusion for 14 days promoted cardiac hypertrophy, and became much more significant for 28 days as shown in S1 File
In parallel with the echocardiography data, LVM/body weight was significantly increased by 16.53% in Ang II infusion for 28 days group compared to the control group (Fig C in S1 File)
Summary
Cardiomyocyte hypertrophy is a maladaptive response to cardiac insults, such as hypertension, myocardial infarction, valvular heart disease, cardiomyopathy, and congenital heart disease. Identifying underlying mechanisms for pathological cardiac hypertrophy is critically important for developing new strategies to protect against heart failure. Gaining a greater understanding of the mechanisms responsible for left ventricular hypertrophy, including intercellular crosstalk of multiple factors implicated in this process, may suggest novel therapeutic strategies. MiRNAs are predicted to regulate approximately one-third of the genome, and are potent mediators of cellular signaling [1]. MiR-133a is the most abundant miRNA and is involved in the regulation of cardiac hypertrophy and failure [5]. Numerous functional roles have been proposed, including regulating myoblast proliferation and differentiation[6], suppressing embryonic cardiomyocyte proliferation[7], preventing genetic cardiac hypertrophy[8], inhibiting cancer[9] and downregulating connective tissue growth factor[10]. The disease-associated profiles of miR-133a expression could be generated in response to hypertrophic stimuli elicited by variations in the activity of intracellular signaling pathways
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