The Antagonism of β3-AR and MICU1 Forms the Key Pathological Mechanism in Cardiac Hypertrophy

Abstract

Mitochondrial calcium uptake 1 (MICU1) serves as a pivotal molecule in maintaining mitochondrial homeostasis, but its concrete role in cardiac hypertrophy remains elusive yet. The β3-adrenergic receptor (β3-AR) has received considerable attention of the world in cardiac hypertrophy, whether it possesses mutual restriction relation with MICU1 deserves further investigation. Specific small interfering RNAs against MICU1 or adenovirus-based plasmid with MICU1 were delivered into left ventricles or incubated with neonatal murine ventricular myocytes (NMVMs) for 48 h. Then, mice were rendered to cardiac hypertrophy by chronic infusion of angiotensin II (Ang-II) with a mini-osmotic pump for 28 days, meanwhile NMVMs were cultured with Ang-II for 48 h. Finally, MICU1 expression was downregulated in hypertrophic myocardium. MICU1 ablation aggravated cardiac hypertrophy both in vivo and in vitro, evidenced by impaired cardiac function, enlarged cardiomyocytes, increased hypertrophic maker genes and enhanced reactive oxygen species (ROS) generation. Moreover, excessive ROS accumulation following MICU1 deficiency increased β3-AR expression, which was reversed by N-acetyl-L-cysteine (NAC). In addition, β3-AR agonists BRL37344 depressed expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and MICU1, leading to aggravated cardiac hypertrophy. However, MICU1 supplementation eliminated those detrimental effects of BRL37344, and decreased the susceptibility of cardiomyocytes to hypertrophic stress. Furthermore, in hypertrophicmyocardium, melatonin alone, but not when combined with luzindole, inhibited β3-AR expression, accompanied with increased expression of PGC-1α/MICU1 and decreased generation of ROS, finally contributing to alleviated cardiac hypertrophy. Conclusively, the mutual antagonism of β3-AR and MICU1 gives rise to pathologic development of cardiac hypertrophy, and melatonin protects against hypertrophic stress by negative regulating the abovementioned pathway. Funding Statement: This work was supported by grants from National Science Funds of China (No.81500208; 81670419), Science Fund for Distinguished Young Scholars of Sichuan Province (No.2017JQ0012), China Postdoctoral Science Foundation (No.2017M613429). Declaration of Interests: The authors state: No competing financial interests exist. Ethics Approval Statement: All experiments performed in adherence to the National Institutes of Health Guidelines on the Use of Laboratory Animals (Bethesda, MD, USA) and conformed to the Institutional Animal Care and Use Committee of Chengdu Military General Hospital.