PKG-1α leucine zipper domain defect increases pulmonary vascular tone: implications in hypoxic pulmonary hypertension
| Autor: | Laura Bach, Ramaswamy Ramchandran, J. Usha Raj, Aarti Raghavan, David L. Geenen, Qiwei Yang, Miranda Sun |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
rho GTP-Binding Proteins Pulmonary Circulation Physiology Vasodilator Agents Drug Evaluation Preclinical Gene Expression Vasodilation Muscle Smooth Vascular Tadalafil Mice chemistry.chemical_compound Lung Cells Cultured Cyclic GMP-Dependent Protein Kinase Type I Ventricular Remodeling Articles Cell Hypoxia medicine.anatomical_structure cardiovascular system Female medicine.symptom Pulmonary and Respiratory Medicine Leucine zipper medicine.medical_specialty Hypertension Pulmonary Myocytes Smooth Muscle Mice Transgenic Pulmonary Artery Biology Nitric oxide Physiology (medical) Internal medicine medicine.artery medicine Animals Ventricular remodeling Hypertrophy Right Ventricular Cell Biology Hypoxia (medical) medicine.disease Pulmonary hypertension Mice Inbred C57BL Endocrinology chemistry Mutation Pulmonary artery Vascular resistance rhoA GTP-Binding Protein Carbolines |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 307:L537-L544 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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-dependent 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-1α [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-1α 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. |
| Databáze: | OpenAIRE |
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