Overexpression of Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α Protects Cardiomyocytes from Lipopolysaccharide-Induced Mitochondrial Damage and Apoptosis

Mitochondrial damage is considered one of the main pathogenetic mechanisms in septic cardiomyopathy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) is critical for maintaining energy homeostasis in different organs and in various physiological and pathological states. It is also a key regulator gene in mitochondrial metabolism. In this study, we investigated whether regulation of the PGC-1 alpha gene had protective effects on septic cardiomyopathy. We developed a rat model of septic cardiomyopathy. H9c2 myocardiocytes were treated with lipopolysaccharide (LPS) and PGC-1 alpha expression measured. PGC-1 alpha-overexpressing lentivirus was used to transfect H9c2 cells. ZLN005 was used to activate PGC-1 alpha. The effect of the inhibition of PGC-1 alpha expression on myocardial cell injury and its underlying mechanisms were also explored. Cell viability was measured by CCK-8 assay. Mitochondrial damage was determined by measuring cellular ATP, reactive oxygen species, and the mitochondrial membrane potential. An apoptosis analysis kit was used to measure cellular apoptosis. Mitochondrial DNA was extracted and real-time PCR performed. LC3B, mitochondrial transcription factor A (TFA), P62, Bcl2, and Bax were determined by immunofluorescence. LC3B, TFA, P62, Parkin, PTEN-induced putative kinase 1, and PGC-1 alpha proteins were determined by Western blotting. We found mitochondrial damage and apoptotic cells in the myocardial tissue of rats with septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1 alpha expression was decreased in the late phase of septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1 alpha activation by ZLN005 andPGC-1 alpha overexpression reduced apoptosis in myocardiocytes after LPS incubation.PGC-1 alpha gene overexpression alleviated LPS-induced cardiomyocyte mitochondrial damage by activating mitochondrial biogenesis and autophagy functions. Our study indicated that mitochondrial damage and apoptosis occurred in septic cardiomyopathy and LPS-treated cardiomyocytes. The low expression level of PGC-1 alpha protein may have contributed to this damage. By activating the expression of PGC-1 alpha, apoptosis was reduced in cardiomyocytes. The underlying mechanism may be that PGC-1 alpha can activate mitochondrial biogenesis and autophagy functions, reducing mitochondrial damage and thereby reducing apoptosis.