PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes
Abstract
Background/Aims: Myocardial ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury is typically marked by calcium overload, disrupted energy metabolism, and necrosis of cardiomyocytes. Previous research demonstrated that chronic intermittent hypobaric hypoxia (CIHH) improves cardiac function during I/R by enhancing cardiac glucose metabolism. However, the precise cellular and molecular mechanisms by which CIHH improves energy metabolism in cardiomyocytes remain unclear. This study investigates whether and how CIHH protects cardiomyocytes from calcium overload and necrosis through energy-regulating pathways.
Methods: Adult male Sprague-Dawley rats were randomly assigned to two groups: control (CON) and CIHH. The CIHH group underwent 28 days of simulated 5,000-meter altitude hypoxia for 6 hours each day in a hypobaric chamber. Rat ventricular myocytes were isolated using enzymatic dissociation. The intracellular calcium concentration ([Ca2+]i) and cTnI protein levels were assessed to evaluate cardiomyocyte injury during and after H/R. mRNA and protein levels associated with cardiac energy metabolism were analyzed using quantitative PCR and Western blotting. PGC-1α gene expression was knocked down using PGC-1α siRNA adenovirus transfection to investigate its role in the energy-regulating pathway.
Results: H/R increased [Ca2+]i and cTnI protein levels in cardiomyocytes. CIHH treatment significantly reduced [Ca2+]i (p<0.01) and cTnI expression (p<0.01) following H/R. Both mRNA and protein levels of PGC-1α were elevated after CIHH treatment, an effect that was reversed by PGC-1α siRNA adenovirus transfection. Additionally, CIHH treatment enhanced the expression of HIF-1α, AMPK, and p-AMPK in cardiomyocytes. Pretreatment with the AMPK inhibitor dorsomorphin blocked the CIHH-induced increase in PGC-1α protein expression (p<0.01). PGC-1α knockdown also prevented the CIHH-induced increase in GLUT4 protein levels (p<0.01) and the decrease in CPT-1b protein levels (p<0.05). Conclusion: CIHH treatment alleviates calcium overload and H/R-induced injury in cardiomyocytes by upregulating PGC-1α expression and modulating glucose and lipid metabolism. The HIF-1α-AMPK signaling pathway appears to play a key role in this protective process.