PKG-1α leucine zipper domain defect increases pulmonary vascular tone: Implications in hypoxic pulmonary hypertension

Ramaswamy Ramchandran, Aarti Raghavan, David Geenen, Miranda Sun, Laura Bach, Qiwei Yang, J. Usha Raj

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Pulmonary hypertension (PH) is a chronic disease characterized by a progressive increase in vasomotor tone, narrowing of the vasculature with structural remodeling, and increase in pulmonary vascular resistance. Current treatment strategies include nitric oxide therapy and methods to increase cGMP-mediated vasodilatation. cGMP-depen-dent protein kinases (PKG) are known mediators of nitric oxide- and cGMP-induced vasodilatation. Deletion of PKG-1 in mice has been shown to induce PH, however, the exact mechanisms by which loss of PKG-1 function leads to PH is not known. In a mouse model with a selective mutation in the NH2-terminus leucine zipper protein interaction domain of PKG-1a [leucine zipper mutant (LZM)], we found a progressive increase in right ventricular systolic pressure and right heart hypertrophy compared with wild-type (WT) mice and increased RhoA-GTPase activity in the lungs. When exposed to chronic hypoxia, LZM mice developed modestly enhanced right ventricular remodeling compared with WT mice. Tadalafil, a phosphodiesterase-5 inhibitor that increases cGMP levels, significantly attenuated hypoxia-induced cardiopulmonary remodeling in WT mice but had no effect in LZM mice. We conclude that a functional leucine zipper domain in PKG-1a is essential for maintenance of a low pulmonary vascular tone in normoxia and for cGMP-mediated beneficial effects of phosphodiesterase-5 inhibition in hypoxic cardiopulmonary remodeling.

Original languageEnglish (US)
Pages (from-to)L537-L544
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume307
Issue number7
DOIs
StatePublished - Oct 1 2014

Keywords

  • 5'-cyclic monophosphate-depen-dent protein kinase
  • Hypoxia
  • Leucine zipper mutant guanosine 3'
  • Phosphodiesterases
  • Pulmonary hypertension and right ventricular hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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