C1q/tumor necrosis factor-related protein-6 exerts protective effects on myocardial ischemia-reperfusion injury through the modulation of the Akt-GSK-3β-Nrf2 signaling cascade.

Abstract

C1q/tumor necrosis factor-related protein-6 (CTRP6) is a multifunctional protein that plays a pivotal role in diverse physiological and pathological processes. To date, whether CTRP6 has a role in myocardial ischemia-reperfusion (I/R) injury remains unexplored. This work aimed to investigate the potential role and mechanism of CTRP6 in myocardial I/R injury through in vitro and in vivo experiments. CTRP6 expression was downregulated in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. The apoptosis, oxidative stress, and inflammation in the H/R-treated cardiomyocytes were markedly alleviated by CTRP6 overexpression or exacerbated by CTRP6 silencing. Notably, the overexpression of CTRP6 remarkably ameliorated the myocardial injury, infarction area, cardiac apoptosis, oxidative stress, and inflammation in mice with myocardial I/R injury in vivo. Further investigation revealed that CTRP6 overexpression enhanced the activation of Nrf2 in the H/R-treated cardiomyocytes and the myocardium tissue of mice with myocardial I/R injury. CTRP6 overexpression increased the phosphorylated level of Akt and GSK-3β, and the inhibition of Akt abolished CTRP6-overexpression-elicited Nrf2 activation in the H/R-treated cardiomyocytes. Additionally, the inhibition of Akt or Nrf2 abolished the protective effects of CTRP6 overexpression on the H/R-treated cardiomyocytes. Altogether, CTRP6 had protective effects on myocardial I/R injury via the effects on the Akt-GSK-3β-Nrf2 signaling cascade. Our work recommends CTRP6 as a novel cardioprotective target for the treatment of myocardial I/R injury.