Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling.

Micrornas (mirnas) play a key role in the development of heart failure,and recent studies have shown that the muscle-specific mir-1 is a key regulator of cardiac hypertrophy. we tested the hypothesis that chronic restoration of mir-1 gene expression in vivo will regress hypertrophy and protect against adverse cardiac remodeling induced by pressure overload. cardiac hypertrophy was induced by left ventricular pressure overload in male sprague-dawley rats subjected to ascending aortic stenosis. when the hypertrophy was established at 2 weeks after surgery,the animals were randomized to receive either an adeno-associated virus expressing mir-1 (aav9.mir-1) or green fluorescent protein (gfp) as control (aav9.gfp) via a single-bolus tail-vein injection. administration of mir-1 regressed cardiac hypertrophy (left ventricular posterior wall thickness,; 2.32±0.08 versus 2.75±0.07 mm,p<0.001) and (left ventricular septum wall thickness,2.23±0.06 versus 2.54±0.10 mm,p<0.05) and halted the disease progression compared with control-treated animals,as assessed by echocardiography (fractional shortening,37.60±5.01% versus 70.68±2.93%,p<0.05) and hemodynamic analyses (end-systolic pressure volume relationship/effective arterial elastance,1.87±0.46 versus 0.96±0.38,p<0.05) after 7 weeks of treatment. additionally,mir-1 replacement therapy lead to a marked reduction of myocardial fibrosis,an improvement in calcium handling,inhibition of apoptosis,and inactivation of the mitogen-activated protein kinase signaling pathways,suggesting a favorable effect on preventing the maladaptive ventricular remodeling. we also identified and validated a novel bona fide target of mir-1,fibullin-2 (fbln2),a secreted protein implicated in extracellular matrix remodeling. taken together,our findings suggest that restoration of mir-1 gene expression is a potential novel therapeutic strategy to reverse pressure-induced cardiac hypertrophy and prevent maladaptive cardiac remodeling.