1. Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure.
- Author
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Cibi DM, Bi-Lin KW, Shekeran SG, Sandireddy R, Tee N, Singh A, Wu Y, Srinivasan DK, Kovalik JP, Ghosh S, Seale P, and Singh MK
- Subjects
- Animals, Atrial Remodeling genetics, Cardiomegaly metabolism, Cardiomyopathy, Hypertrophic metabolism, Cell Line, DNA-Binding Proteins metabolism, Disease Models, Animal, Female, Heart Failure metabolism, Histone-Lysine N-Methyltransferase metabolism, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mitochondria metabolism, Mitochondrial Diseases genetics, Mitochondrial Diseases metabolism, Myocytes, Cardiac metabolism, Rats, Transcription Factors metabolism, Cardiomegaly genetics, DNA-Binding Proteins genetics, Heart Failure genetics, Transcription Factors genetics
- Abstract
Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N-methyltransferase factors (Ehmts) act together to reduce expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of the pro-hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Our study demonstrates that Prdm16 protects the heart against age-dependent cardiac hypertrophy and heart failure., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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