MiR-124 aggravates failing hearts by suppressing CD151-facilitated angiogenesis in heart.

Yanru Zhao,Dao Wen Wang,Houjuan Zuo,Wei Gong,Xin A Zhang,Huaping Li,Mengwen Yan,Jiahui Fan,Chen Chen,Zhongwei Yin

doi:10.18632/oncotarget.24205

Abstract

Heart failure (HF) is the final common pathway of various cardiovascular diseases. Although it is well documented that reduction of cardiac angiogenesis contributes to the progression from adaptive cardiac hypertrophy to HF, the molecular mechanisms remain unknown. In the present study, we found that cardiac expression of miR-124 was increased in patients and mice with HF. Recombinant adeno-associated virus (rAAV)-mediated miR-124 over-expression aggravated angiotensin II (Ang II) infusion-induced cardiac dysfunction and abnormal cardiac angiogenesis in mice. In vitro, transfection of miR-124 mimics significantly promoted apoptosis and reduced viability, migration, tube formation, and nitric oxide release in endothelial cells. In addition, CD151 was identified as a direct target of miR-124. Endothelial cell injury caused by CD151 silencing was mimicked by miR-124 over-expression. Re-expression of CD151 attenuated miR-124-mediated suppression of cardiac angiogenesis and cardiac dysfunction in Ang II-treated mice. Our observations suggest that miR-124 is an important negative regulator of cardiac angiogenesis and cardiac function, likely by suppressing the expression of CD151 in heart cells. Modulation of miR-124 levels may provide new strategies and targets for HF therapy.

Highlights

Heart failure (HF) is a final common consequence of numerous cardiovascular diseases, and a major global healthcare problem [1]
The results showed that left ventricular (LV) ejection fraction (EF), percentage of fractional shortening (FS), and ±dp/dt were impaired with angiotensin II (Ang II)-infusion (Figure 2B–2D). Recombinant adeno-associated virus (rAAV)-miR-124 treatment further exacerbated the cardiac dysfunction, while downregulation of miR-124 by rAAVmiR-124 tough decoy RNAs (TuDs) alleviated the impairment (Figure 2B–2D)
We identified miR-124mediated impairment of cardiac angiogenesis by targeting CD151 in HF

Summary

Introduction

Heart failure (HF) is a final common consequence of numerous cardiovascular diseases, and a major global healthcare problem [1]. Cardiac hypertrophy is an adaptive response of the heart against different stressors, but prolonged cardiac hypertrophy leads to HF [4]. Disruption of capillary angiogenesis in the hypertrophied heart plays an important role in the process from adaptive hypertrophy to decompensated HF [5]. During the progression of cardiac hypertrophy, proportional growth of capillaries is required by the increased metabolic and oxygen demands of growing cardiac myocytes. Coronary angiogenesis was enhanced during the initial phase of adaptive cardiac hypertrophy, but reduced as the heart underwent continuous pathological remodeling [6], which could lead to myocardial ischemia and deterioration of hypertrophy

Methods

Results

Conclusion