SIRT1 is required for mitochondrial biogenesis reprogramming in hypoxic human pulmonary arteriolar smooth muscle cells.
Although recent studies have reported that mitochondria are putative oxygen sensors underlying hypoxic pulmonary vasoconstriction, little is known concerning the sirtuin 1 (SIRT1)-mediated mitochondrial biogenesis regulatory program in pulmonary arteriolar smooth muscle cells (PASMCs) during hypoxia/reoxygenation (H/R). We investigated the epigenetic regulatory mechanism of mitochondrial biogenesis and function in human PASMCs during H/R. Human PASMCs were exposed to hypoxia of 24-48 h and reoxygenation of 24-48 h. The expression of SIRT1 was reduced in a time-dependent manner. Mitochondrial transcription factor A (TFAM) expression was increased during hypoxia and decreased during reoxygenation, while the release of TFAM was increased in a time-dependent manner. Lentiviral overexpression of SIRT1 preserved SIRT3 deacetylase activity in human PASMCs exposed to H/R. Knockdown of PGC-1α suppressed the effect of SIRT1 on SIRT3 activity. Knockdown of SIRT3 abrogated SIRT1-mediated deacetylation of cyclophilin D (CyPD). Notably, knockdown of SIRT3 or PGC-1α suppressed the incremental effect of SIRT1 on mitochondrial TFAM, mitochondrial DNA (mtDNA) content and cellular ATP levels. Importantly, polydatin restored SIRT1 levels in human PASMCs exposed to H/R. Knockdown of SIRT1 suppressed the effect of polydatin on mitochondrial TFAM, mtDNA content and cellular ATP levels. In conclusion, SIRT1 expression is decreased in human PASMCs during H/R. TFAM expression in mitochondria is reduced and the release of TFAM is increased by H/R. PGC-1α/SIRT3/CyPD mediates the protective effect of SIRT1 on expression and release of TFAM and mitochondrial biogenesis and function. Polydatin improves mitochondrial biogenesis and function by enhancing SIRT1 expression in hypoxic human PASMCs.
Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Pengyun
P
Li
Department of Pharmacy, Henan Medical College, Zhengzhou, Henan 450046, P.R. China.
Yan
Y
Liu
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
Nana
N
Burns
Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Ke-Seng
KS
Zhao
Guangdong Key Laboratory of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Rui
R
Song
D015415:Biomarkers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D004268:DNA-Binding Proteins; D005960:Glucosides; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013267:Stilbenes; C499631:TFAM protein, human; D014157:Transcription Factors; D056564:Sirtuin 1; D056566:Sirtuin 3; C058229:polydatin