Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway.

Abstract

Mitochondrial calcium uptake 1 (MICU1) is a pivotal molecule in maintaining mitochondrial homeostasis under stress conditions. However, it is unclear whether MICU1 attenuates mitochondrial stress in angiotensin II (Ang-II)-induced cardiac hypertrophy or if it has a role in the function of melatonin. Here, small-interfering RNAs against MICU1 or adenovirus-based plasmids encoding MICU1 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) for 48 h. MICU1 expression was depressed in hypertrophic myocardia and MICU1 knockdown aggravated Ang-II-induced cardiac hypertrophy in vivo and in vitro. In contrast, MICU1 upregulation decreased cardiomyocyte susceptibility to hypertrophic stress. Ang-II administration, particularly in NMVMs with MICU1 knockdown, led to significantly increased reactive oxygen species (ROS) overload, altered mitochondrial morphology, and suppressed mitochondrial function, all of which were reversed by MICU1 supplementation. Moreover, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)/MICU1 expression in hypertrophic myocardia increased with melatonin. Melatonin ameliorated excessive ROS generation, promoted mitochondrial function, and attenuated cardiac hypertrophy in control but not MICU1 knockdown NMVMs or mice. Collectively, our results demonstrate that MICU1 attenuates Ang-II-induced cardiac hypertrophy by inhibiting mitochondria-derived oxidative stress. MICU1 activation may be the mechanism underlying melatonin-induced protection against myocardial hypertrophy.

• Authors: Yi Yang, Jin Du, Rui Xu, Yang Shen, Dachun Yang, De Li, Houxiang Hu, Haifeng Pei, Yongjian Yang
• Journal: Aging (Aging (Albany NY)) Vol. 13 Issue 1 Pg. 493-515 (11 26 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 33259334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Calcium-Binding Proteins
• MICU1 protein, mouse
• Mitochondrial Membrane Transport Proteins
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Reactive Oxygen Species
• Vasoconstrictor Agents
• Angiotensin II
• Melatonin

Topics

• Angiotensin II (toxicity)
• Animals
• Antioxidants (pharmacology)
• Calcium-Binding Proteins (drug effects, genetics, metabolism)
• Cardiomegaly (chemically induced, genetics, metabolism)
• Disease Models, Animal
• Gene Knockdown Techniques
• Heart (drug effects)
• In Vitro Techniques
• Melatonin (pharmacology)
• Mice
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (drug effects, genetics, metabolism)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects, genetics)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (drug effects, metabolism)
• Reactive Oxygen Species (metabolism)
• Vasoconstrictor Agents (toxicity)