Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery

Am J Physiol Lung Cell Mol Physiol. 2012 Jul 1;303(1):L64-74. doi: 10.1152/ajplung.00002.2012. Epub 2012 May 11.

Abstract

Persistent hypoxic pulmonary vasoconstriction (HPV) plays a significant role in the pathogenesis of pulmonary hypertension, which is an emerging clinical problem around the world. We recently showed that hypoxia-induced activation of glucose-6-phosphate dehydrogenase (Glc-6-PD) in pulmonary artery smooth muscle links metabolic changes within smooth muscle cells to HPV and that inhibition of Glc-6PD reduces acute HPV. Here, we demonstrate that exposing pulmonary arterial rings to hypoxia (20-30 Torr) for 12 h in vitro significantly (P < 0.05) reduces (by 30-50%) SM22α and smooth muscle myosin heavy chain expression and evokes HPV. Glc-6-PD activity was also elevated in hypoxic pulmonary arteries. Inhibition of Glc-6-PD activity prevented the hypoxia-induced reduction in SM22α expression and inhibited HPV by 80-90% (P < 0.05). Furthermore, Glc-6-PD and protein kinase G (PKG) formed a complex in pulmonary artery, and Glc-6-PD inhibition increased PKG-mediated phosphorylation of VASP (p-VASP). In turn, increasing PKG activity upregulated SM22α expression and attenuated HPV evoked by Glc-6-PD inhibition. Increasing passive tension (from 0.8 to 3.0 g) in hypoxic arteries for 12 h reduced Glc-6-PD, increased p-VASP and SM22α levels, and inhibited HPV. The present findings indicate that increases in Glc-6-PD activity influence PKG activity and smooth muscle cell phenotype proteins, all of which affect pulmonary artery contractility and remodeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cattle
  • Cell Hypoxia / physiology
  • Cyclic GMP-Dependent Protein Kinases / genetics*
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Down-Regulation
  • Endothelium, Vascular / metabolism
  • Glucosephosphate Dehydrogenase / genetics*
  • Glucosephosphate Dehydrogenase / metabolism*
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / pathology
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / physiology*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / physiology*
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Phenotype
  • Phosphorylation / genetics
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / physiology*
  • Vasoconstriction / genetics
  • Vasoconstriction / physiology

Substances

  • Biomarkers
  • Microfilament Proteins
  • Muscle Proteins
  • transgelin
  • Glucosephosphate Dehydrogenase
  • Cyclic GMP-Dependent Protein Kinases
  • Myosin Heavy Chains