Pachymic acid (PA) inhibits ferroptosis of cardiomyocytes via activation of the AMPK in mice with ischemia/reperfusion‐induced myocardial injury

Abstract

AbstractPachymic acid (PA) is a lanostane‐type triterpenoid with various pharmacological effects. However, little is known about the effect of PA on myocardial infarction (MI) induced by ischemia/reperfusion (I/R). In this study, we aimed to investigate the protective effect of PA and its underlying mechanism. A cellular MI model was established by oxygen‐glucose deprivation and reperfusion (OGD/R) treatment in HL‐1 cardiomyocytes, and we found that OGD/R treatment decreased cell viability and glutathione peroxide (GSH‐Px) activity, increased Fe2+ concentration and lactate dehydrogenase (LDH) activity, promoted malondialdehyde (MDA) and reactive oxygen species (ROS) production, and inhibited the expression of ferroptosis marker proteins SLC7A11 and GPX4 in a time‐dependent manner. OGD/R‐induced HL‐1 cells were pretreated with different concentrations of PA (0, 20, 40, 60 μg/mL) for 24 h, and toxicological experiments showed that 150 μg/mL PA decreased cell viability, while low concentrations of PA had no toxic effect on cells. 20 μg/mL PA reversed the inhibitory effect of OGD/R on cell viability, reduced MDA and ROS production, and Fe2+ accumulation, increased GSH‐Px activity and the expression of SLC7A11 and GPX4, and decreased LDH activity, especially at 60 μg/mL PA. Meanwhile, PA promoted the phosphorylation of IRS‐1, AKT, and AMPK proteins in a dose‐dependent manner. AICAR, an AMPK activator, inhibited ferroptosis, while STO‐609, an AMPK inhibitor, largely abolished the effect of PA on OGD/R‐induced ferroptosis of HL‐1 cells. In addition, PA inhibited ferroptosis and myocardial I/R injury in wild‐type mice and AMPK knockout (AMPK−/−) mice. Collectively, PA inhibited ferroptosis of cardiomyocytes through activating of the AMPK pathway, thereby alleviating myocardial I/R injury in mice.