Abstract

Background: Physiological cardiac hypertrophy occurs commonly in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure . Although physiological and pathological hypertrophy often involve distinct signaling mechanisms, miR-222 is an exercise-induced microRNA that is required for physiological hypertrophy but is also induced in pathological hypertrophy. Here, we sought to define the role of miR-222 in pathological hypertrophy. Methods and Results: We generated miR-222 gain-of-function (GOF) models through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) or somatic expression with AAV9-miR-222. Loss-of-function (LOF) was achieved using a locked nucleic antimiR (LNA) specific for miR-222. miR-222 GOF and LOF models manifested normal cardiac structure and function at baseline. After transverse aortic constriction (TAC), TgC-miR-222 had less pathological hypertrophy as well as better cardiac function (FS = 37.9% vs 28.7%, p<0.01) and survival (median survival = 120 days vs 54 days, p<0.05). Similarly, AAV9-miR-222 gene transfer immediately after TAC also better preserved cardiac function. Conversely, LNA-anti-miR-222 dramatically exacerbated pathological hypertrophy, cardiac dysfunction, and heart failure (FS = 24.4% vs 35.3%, p<0.01) after TAC. PUMA, a pro-apoptotic Bcl-2 family member and two transcription factors, Hmbox1 and NFATc3, were identified as novel, direct miR-222 targets contributing to its roles in this context. Conclusions: Although miR-222 is upregulated in both physiological and pathological hypertrophy, its roles in these conditions are quite different. In response to pressure overload, miR-222 inhibits pathological hypertrophy, adverse remodeling, and cardiac dysfunction. These findings reinforce the conceptual model that physiological and pathological hypertrophy are qualitatively distinct, rather than differing only in degree. Further, they suggest that miR-222 may hold promise as a potential therapeutic target in pathological cardiac hypertrophy and heart failure.

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