miR-222 inhibits pathological cardiac hypertrophy and heart failure

Author:

Liu Xiaojun1,Li Haobo2,Hastings Margaret H3,Xiao Chunyang1,Damilano Federico1,Platt Colin1,Lerchenmüller Carolin145,Zhu Han16,Wei Xin Paul1,Yeri Ashish1,Most Patrick4,Rosenzweig Anthony3ORCID

Affiliation:

1. Corrigan-Minehan Heart Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02114 , USA

2. Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital , Boston, MA 02114 , USA

3. Institute for Heart and Brain Health, University of Michigan Medical Center , North Campus Research Complex, 2800 Plymouth Rd, NCRC Building 25, Ann Arbor, MI 48109-2800 , USA

4. Department of Cardiology, Angiology, Pulmonology, University Hospital Heidelberg , INF 410, 69120 Heidelberg , Germany

5. German Center for Heart and Cardiovascular Research (DZHK), Heidelberg/Mannheim , INF 410, 69120 Heidelberg , Germany

6. Stanford Cardiovascular Institute, Stanford School of Medicine , Stanford, CA 94305 , USA

Abstract

Abstract Aims Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy. Methods and results We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified p53-up-regulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and nuclear factor of activated T-cells 3, as direct miR-222 targets contributing to its roles in this context. Conclusion While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodelling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest that miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.

Funder

American Heart Association

National Institutes of Health

German Center for Cardiovascular Research

Medical Faculty of Heidelberg University Medical School

Else-Kröner-Fresenius Stiftung

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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