TY - JOUR
T1 - Protein kinase G-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation
AU - Zhao, Yidan D.
AU - Cai, Lei
AU - Mirza, Muhammad K.
AU - Huang, Xiaojia
AU - Geenen, Dave L.
AU - Hofmann, Franz
AU - Yuan, Jason X J
AU - Zhao, You Yang
N1 - Funding Information:
Supported by grants from the NIH ( R01HL085462 and R01HL085462-3S1 to Y.Y.Z.).
PY - 2012/6
Y1 - 2012/6
N2 - Protein kinase G (PKG) plays an important role in the regulation of vascular smooth cell contractility and is a critical mediator of nitric oxide signaling, which regulates cardiovascular homeostasis. PKG-I-knockout (Prkg1 -/-) mice exhibit impaired nitric oxide/cGMP-dependent vasorelaxation and systemic hypertension. However, it remains unknown whether PKG-I deficiency induces pulmonary hypertension. In this study, we characterized the hypertensive pulmonary phenotypes in Prkg1 -/- mice and delineated the underlying molecular basis. We observed a significant increase in right ventricular systolic pressure in Prkg1 -/- mice in the absence of systemic hypertension and left-sided heart dysfunction. In addition, we observed marked muscularization of distal pulmonary vessels in Prkg1 -/- mice. Microangiography revealed impaired integrity of the pulmonary vasculature in Prkg1 -/- mice. Mechanistically, PKG-I-mediated phosphorylation of Rho A Ser188 was markedly decreased, and the resultant Rho A activation was significantly increased in Prkg1 -/- lung tissues, which resulted in Rho kinase activation. The i.t. administration of fasudil, a Rho kinase inhibitor, reversed the hypertensive pulmonary phenotype in Prkg1 -/- mice. Taken together, these data show that PKG-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation-mediated vasoconstriction and pulmonary vascular remodeling.
AB - Protein kinase G (PKG) plays an important role in the regulation of vascular smooth cell contractility and is a critical mediator of nitric oxide signaling, which regulates cardiovascular homeostasis. PKG-I-knockout (Prkg1 -/-) mice exhibit impaired nitric oxide/cGMP-dependent vasorelaxation and systemic hypertension. However, it remains unknown whether PKG-I deficiency induces pulmonary hypertension. In this study, we characterized the hypertensive pulmonary phenotypes in Prkg1 -/- mice and delineated the underlying molecular basis. We observed a significant increase in right ventricular systolic pressure in Prkg1 -/- mice in the absence of systemic hypertension and left-sided heart dysfunction. In addition, we observed marked muscularization of distal pulmonary vessels in Prkg1 -/- mice. Microangiography revealed impaired integrity of the pulmonary vasculature in Prkg1 -/- mice. Mechanistically, PKG-I-mediated phosphorylation of Rho A Ser188 was markedly decreased, and the resultant Rho A activation was significantly increased in Prkg1 -/- lung tissues, which resulted in Rho kinase activation. The i.t. administration of fasudil, a Rho kinase inhibitor, reversed the hypertensive pulmonary phenotype in Prkg1 -/- mice. Taken together, these data show that PKG-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation-mediated vasoconstriction and pulmonary vascular remodeling.
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U2 - 10.1016/j.ajpath.2012.02.016
DO - 10.1016/j.ajpath.2012.02.016
M3 - Article
C2 - 22632818
AN - SCOPUS:84861632141
SN - 0002-9440
VL - 180
SP - 2268
EP - 2275
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -
