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) |
|---|---|
| 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 |
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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
Cite this
PKG-1α leucine zipper domain defect increases pulmonary vascular tone : Implications in hypoxic pulmonary hypertension. / Ramchandran, Ramaswamy; Raghavan, Aarti; Geenen, David; Sun, Miranda; Bach, Laura; Yang, Qiwei; Usha Raj, J.
In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 307, No. 7, 01.10.2014, p. L537-L544.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PKG-1α leucine zipper domain defect increases pulmonary vascular tone
T2 - Implications in hypoxic pulmonary hypertension
AU - Ramchandran, Ramaswamy
AU - Raghavan, Aarti
AU - Geenen, David
AU - Sun, Miranda
AU - Bach, Laura
AU - Yang, Qiwei
AU - Usha Raj, J.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
AB - 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.
KW - 5'-cyclic monophosphate-depen-dent protein kinase
KW - Hypoxia
KW - Leucine zipper mutant guanosine 3'
KW - Phosphodiesterases
KW - Pulmonary hypertension and right ventricular hypertrophy
UR - http://www.scopus.com/inward/record.url?scp=84907494666&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907494666&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00093.2014
DO - 10.1152/ajplung.00093.2014
M3 - Article
C2 - 25128522
AN - SCOPUS:84907494666
VL - 307
SP - L537-L544
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 7
ER -