Protein Kinase G-I Deficiency Induces Pulmonary Hypertension through Rho A/Rho Kinase Activation

Protein Kinase G (PKG) is a critical mediator of nitric oxide signaling which regulates cardiovascular homeostasis. It has been shown that 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. Here we characterize the hypertensive pulmonary phenotypes in Prkg1-/- mice and delineate the underlying molecular basis. We observed significant increase in right ventricular systolic pressure in Prkg1-/- mice in the absence of systemic hypertension and left heart dysfunction. We also 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 resultant Rho A activation was significantly increased in Prkg1-/- lung tissues, which results in Rho kinase activation. Intra-tracheal administration of Fasudil, a Rho kinase inhibitor reversed the hypertensive pulmonary phenotype in Prkg1-/- mice. Together, these data show that PKG-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation-mediated vasoconstriction and pulmonary vascular remodeling.