Protein kinase G-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation.
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.
Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois; Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612, USA. yidanzhao@gmail.com
Yidan D
YD
Zhao
Lei
L
Cai
Muhammad K
MK
Mirza
Xiaojia
X
Huang
Dave L
DL
Geenen
Franz
F
Hofmann
Jason X-J
JX
Yuan
You-Yang
YY
Zhao
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000959:Antihypertensive Agents; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D020742:rhoA GTP-Binding Protein; C049347:fasudil