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 language | English (US) |
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Pages (from-to) | L537-L544 |
Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
Volume | 307 |
Issue number | 7 |
DOIs | |
State | Published - Oct 1 2014 |
Externally published | Yes |
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