miR-106a promotes cardiac hypertrophy by targeting mitofusin 2.

Pathological cardiac hypertrophy is a main factor leading to heart failure and associated sudden death. Improved understanding of the underlying molecular mechanisms should aid better treatment of the disease. This study aimed to test our hypothesis that a microRNA miR-106a played an important role in the development of cardiac hypertrophy through targeting mitofusin 2 (Mfn2), a mitochondrial fusion protein known to be critical in regulating cardiac function. miR-106a was robustly upregulated in hypertrophied myocardium both in vivo and in vitro. Forced transient expression of miR-106a in otherwise healthy cardiomyocytes induced the hypertrophic phenotypes resembling those produced by angiotensin II (AngII) exposure. Knockdown of miR-106a by its specific inhibitor nearly completely reversed the hypertrophic phenotypes induced by AngII pretreatment and pressure overload. On the other hand, Mfn2 was markedly downregulated in hypertrophic heart and cardiomyocytes, which was in reciprocal to expression of miR-106a. Mfn2 was experimentally validated as a direct target gene for miR-106a. Overexpression of Mfn2 counteracted the hypertrophic responses induced by miR-106a, whereas silence of Mfn2 by its siRNA abolished the anti-hypertrophic property of miR-106a inhibitor. Furthermore, overexpression of Mfn2 alleviated the hypertrophic phenotypes induced by AngII in cultured cardiomyocytes, while Mfn2 siRNA alone was able to induce hypertrophic changes in cultured cardiomyocytes. Moreover, AngII and miR-106a treatment cultured cardiomyocytes mitochondria presented cristae defects, considerable depolarization of mitochondrial membrane and increased ROS production. These alterations were reversed by miR-106a inhibitor or overexpression of Mfn2. Taken together, our findings indicate miR-106a as an important factor to promote hypertrophic progress and suggest miR-106a as a new molecular target for the treatment of pathological hypertrophy. The present study also uncovered a novel relationship between miR-106a and Mfn2, with Mfn2 as a downstream signaling mediator of miR-106a.