Abstract
MicroRNA-208a (mir-208a) is essential for cardiac hypertrophy and fibrosis. Endoglin, a co-receptor of transforming growth factor-β is also essential for cardiac fibrosis. Endoglin has been shown to be a target of mir-208a in the in vitro mechanical stress model. Volume overload can lead to heart failure and cardiac fibrosis. The role of mir-208a and endoglin in volume overload heart failure is well known. We sought to investigate the mechanism of regulation of mir-208a and endoglin in volume overload-induced heart failure. Aorta-caval (AV) shunt was performed in adult Sprague-Dawley rats to induce volume overload. Heart weight and heart weight/body weight ratio significantly increased in AV shunt animals. AV shunt significantly increased left ventricular end-diastolic dimension as compared to sham group. Mir-208a was significantly induced by AV shunt from 3 to 14 days. Endoglin, myosin heavy chain-β and brain natriuretic peptide were significantly induced by AV shunt from 3 to 14 days. Overexpression of mir-208a in the sham group without AV shunt significantly increased endoglin expression similar to the AV shunt group. Antagomir-208a attenuated the endoglin expression induced by AV shunt. Pretreatment with atorvastatin also attenuated the endoglin expression induced by AV shunt. AV shunt significantly increased myocardial fibrosis as compared to sham group. Overexpression of mir-208a in the sham group significantly increased myocardial fibrosis. Antagomir-208a and atorvastatin significantly attenuated the myocardial fibrosis induced by AV shunt. In conclusion, mir-208a increased endoglin expression to induce myocardial fibrosis in volume overloaded heart failure. Treatment with atorvastatin can attenuate the myocardial fibrosis induced by volume overload through inhibition of endoglin expression.
Highlights
Cardiac fibrosis is closely associated with heart failure because cardiac fibrosis may cause the loss of normal cardiac function [1]
LV end-diastolic and end-systolic dimension significantly increased after AV shunt for 14 days and inter-ventricular septum thickness and left ventricular posterior wall thickness did not significantly change, indicating the volumeoverload induced by AV shunt
The mir-208a level was still higher in the atorvastatin-treated group than in the sham group, indicating that atorvastatin partially but not completely inhibited the increase of mir-208a expression induced by AV shunt
Summary
Cardiac fibrosis is closely associated with heart failure because cardiac fibrosis may cause the loss of normal cardiac function [1]. Endoglin is a potent mediator of profibrotic effects of angiotensin II on cardiac fibroblasts [3] and can modulate the effect of TGFb1 on extracellular matrix synthesis [4]. These data indicate that endoglin plays an important role in fibrogenesis in cardiac remodeling. Place et al have demonstrated mir functioning to induce gene expression [6]. Because of their capability to monitor the expression levels of the genes that control both adaptive and maladaptive cardiac remodeling processes, mirs may be vitally involved in the pathogenesis of heart failure [7,8]. Since volume overload can lead to heart failure and myocardial fibrosis, we sought to investigate the regulation of mir-208a in volume overloading heart
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