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

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Abstract

Mitochondrial damage is considered one of the main pathogenetic mechanisms in septic cardiomyopathy. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) 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-1α gene had protective effects on septic cardiomyopathy. We developed a rat model of septic cardiomyopathy. H9c2 myocardiocytes were treated with lipopolysaccharide (LPS) and PGC-1α expression measured. PGC-1α-overexpressing lentivirus was used to transfect H9c2 cells. ZLN005 was used to activate PGC-1α. The effect of the inhibition of PGC-1α 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-1α 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-1α expression was decreased in the late phase of septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α activation by ZLN005 and PGC-1α overexpression reduced apoptosis in myocardiocytes after LPS incubation. PGC-1α 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-1α protein may have contributed to this damage. By activating the expression of PGC-1α, apoptosis was reduced in cardiomyocytes. The underlying mechanism may be that PGC-1α can activate mitochondrial biogenesis and autophagy functions, reducing mitochondrial damage and thereby reducing apoptosis.

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Abbreviations

LPS:

Lipopolysaccharide

HE:

Hematoxylin-eosin staining

RT-PCR:

Real-time polymerase chain reaction

MAP:

Mean artery pressure

LVEDP:

Left ventricular end-diastolic pressure

PGC-1α:

Peroxisome proliferator activated receptor gamma coactivator 1 alpha

ROS:

Reactive oxygen species

mtDNA:

Mitochondrial DNA

PINK1:

PTEN-induced putative kinase 1

mt-Tfam:

Mitochondrial expression of transcription factors

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Funding

This study’s reagents cost was supported by the National Natural Science Foundation of China (No. 81971810). This study’s animals cost was supported by the Natural Science Foundation of Liaoning Province (No. 2017225003, No. 2018108001). This study’s experimental apparatus cost was supported by the Science and Technology Foundation of Shenyang (No. F13-220-9-38) and 345 Talent Project of Sheng**g Hospital of China Medical University.

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Authors and Affiliations

  1. Department of Pediatrics, PICU, Sheng**g Hospital of China Medical University, No. 36, SanHao Street, Shenyang, Liaoning, 110004, People’s Republic of China

    Tao Zhang, Chun-Feng Liu, Tie-Ning Zhang, Ri Wen & Wen-Liang Song

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  1. Tao Zhang
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  2. Chun-Feng Liu
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  3. Tie-Ning Zhang
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  4. Ri Wen
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Contributions

T.Z. and C.F.L. conceived and designed the study. T.Z. performed the most assays. T.Z., R.W., and W.L.S analyzed the data. T.Z., T.N.Z, and C.F.L wrote the manuscript.

Corresponding author

Correspondence to Chun-Feng Liu.

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The authors declare that they have no conflict of interests.

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The study was approved by the Ethics Committee of Sheng**g Hospital of China Medical University(2018PS121k).

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Zhang, T., Liu, CF., Zhang, TN. et al. Overexpression of Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α Protects Cardiomyocytes from Lipopolysaccharide-Induced Mitochondrial Damage and Apoptosis. Inflammation 43, 1806–1820 (2020). https://doi.org/10.1007/s10753-020-01255-4

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