Testosterone can affect cardiovascular disease, but its effects on mitochondrial dynamics in the post-infarct myocardium remain unclear. To observe the effects of testosterone replacement, a rat model of castration-myocardial infarction (MI) was established by ligating the left anterior descending coronary artery 2 weeks after castration with or without testosterone treatment. Expression of mitochondrial fission and fusion proteins was detected by western blot and immunofluorescence 14 days after MI. Cardiac function, myocardial inflammatory infiltration and fibrosis, cardiomyocyte apoptosis, mitochondrial microstructure, and ATP levels were also assessed. Compared with MI rats, castrated rats showed aggravated mitochondrial and myocardial insults, including mitochondrial swelling and disordered arrangement; loss of cristae, reduced mitochondrial length; decreased ATP levels; cardiomyocyte apoptosis; and impaired cardiac function. Results of western blotting analyses indicated that castration downregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) and mitofusin 2, but upregulated dynamin-related protein 1. The results were also supported by results obtained using immunofluorescence. However, these detrimental effects were reversed by testosterone supplementation, which also elevated the upstream AMP-activated protein kinase (AMPK) activation of PGC1A. Thus, testosterone can protect mitochondria in the post-infarct myocardium, partly via the AMPK–PGC1A pathway, thereby decreasing mitochondrial dysfunction and cardiomyocyte apoptosis. The effects of testosterone were confirmed by the results of ELISA analyses.
Fengyue Wang, Jing Yang, Junfeng Sun, Yanli Dong, Hong Zhao, Hui Shi, and Lu Fu
Lu Fu, Hongyuan Zhang, Jeremiah Ong’achwa Machuki, Tingting Zhang, Lin Han, Lili Sang, Lijuan Wu, Zhiwei Zhao, Matthew James Turley, Xide Hu, Hongjian Hou, Dongye Li, Sian E Harding, and Hong Sun
Currently, there are no conventional treatments for stress-induced cardiomyopathy (SCM, also known as Takotsubo syndrome), and the existing therapies are not effective. The recently discovered G protein- coupled estrogen receptor (GPER) executes the rapid effects of estrogen (E2). In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose of Epi in adult rats and human-induced pluripotent stem cells–derived cardiomyocytes(hiPSC-CMs). (1) GPER activation with agonist G1/ E2 prevented an increase in left ventricular internal diameter at end-systole, the decrease both in ejection fraction and cardiomyocyte shortening amplitude elicited by Epi. (2) G1/ E2 mitigated heart injury induced by Epi, as revealed by reduced plasma brain natriuretic peptide and lactate dehydrogenase release into culture supernatant. (3) G1/E2 prevented the raised phosphorylation and internalization of β2-adrenergic receptors（β2AR）. (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cyclic adenosine monophosphate concentration in culture supernatant treated with Epi. (5) G1/E2 rescued decreased Ca2+ amplitude and Ca2+ channel current (ICa-L) in rat cardiomyocytes. Notably, the above effects of E2 were blocked by the GPER antagonist, G15. In hiPSC-CM (which expressed GPER, β1AR and β2ARs), knockdown of GPER by siRNA abolished E2 effects on increasing ICa-L and action potential duration in the stress state. In conclusion, GPER played a protective role against SCM. Mechanistically, this effect was mediated by balancing the coupling of β2AR to the Gαs and Gαi signalling pathways.