Background: Micro RNA s (mi RNA s) 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. Methods and Results: Cardiac hypertrophy was induced by left ventricular pressure overload in male S prague‐ D awley 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 ( AAV 9. miR‐1 ) or green fluorescent protein ( GFP ) as control ( AAV 9. 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. Conclusions: 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.

Dysregulation of endoplasmic reticulum (ER) Ca²⁺ homeostasis triggers ER stress leading to the development of insulin resistance in obesity and diabetes. Impaired function of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) has emerged as a major contributor to ER stress. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel allosteric activator, CDN1163, which markedly lowered fasting blood glucose, improved glucose tolerance, and ameliorated hepatosteatosis but did not alter glucose levels or body weight in lean controls. Importantly, CDN1163-treated ob/ob mice maintained euglycemia comparable with that of lean mice for >6 weeks after cessation of CDN1163 administration. CDN1163-treated ob/ob mice showed a significant reduction in adipose tissue weight with no change in lean mass, assessed by magnetic resonance imaging. They also showed an increase in energy expenditure using indirect calorimetry, which was accompanied by increased expression of uncoupling protein 1 (UCP1) and UCP3 in brown adipose tissue. CDN1163 treatment significantly reduced the hepatic expression of genes involved in gluconeogenesis and lipogenesis, attenuated ER stress response and ER stress-induced apoptosis, and improved mitochondrial biogenesis, possibly through SERCA2-mediated activation of AMP-activated protein kinase pathway. The findings suggest that SERCA2b activation may hold promise as an effective therapy for type-2 diabetes and metabolic dysfunction.