The key role of PGC-1α in mitochondrial biogenesis and the proliferation of pulmonary artery vascular smooth muscle cells at an early stage of hypoxic exposure

Mol Cell Biochem. 2012 Aug;367(1-2):9-18. doi: 10.1007/s11010-012-1313-z. Epub 2012 Apr 15.

Abstract

Peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) induced by hypoxia regulates mitochondrial biogenesis and oxidative stress. However, the potential role of PGC-1α in hypoxia-promoted proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is completely unknown. In this study, we found that hypoxia significantly induced the expression of PGC-1α in cultured PASMCs and activated mitochondrial biogenesis through upregulation of nuclear respiratory factor-1 and mitochondria transcription factor A in a time-dependent manner. Knockdown of PGC-1α by siRNA abrogated hypoxia-induced PASMCs proliferation via the downregulation of PCNA, cyclinA, and cyclinE. Furthermore, we observed that PI3K/Akt signaling pathway was involved in hypoxia induced PGC-1α expression and PASMCs proliferation. Taken together, these datas reveal PGC-1α as the key regulator to mediate mitochondrial biogenesis and the proliferation of PASMCs at an early stage of hypoxic exposure. This process might bring to light a potential adaptive mechanism for PASMCs to minimize hypoxic damage and our novel findings provide new insight into the development of hypoxic pulmonary hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclins / genetics
  • Cyclins / metabolism
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Male
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / physiology*
  • Mitochondria, Muscle / ultrastructure
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / physiology
  • Myocytes, Smooth Muscle / ultrastructure
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Artery / cytology*
  • RNA Interference
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation

Substances

  • Cyclins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • RNA-Binding Proteins
  • Transcription Factors
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt