• Not Applicable

In this preclinical study, the authors hypothesised that deficiency of protein kinase G-1 (PKG-1), a serine/threonine kinase, would induce pulmonary hypertension (PH) in mice through Rho A/Rho kinase activation.

Protein kinase G-1- knockout (Prkg1^−/−) mice had decreased PKG-1 and increased pulmonary artery systolic pressure compared to wild type mice. Prkg1^−/− mice had marked microvascular remodelling and precapillary occlusion in the lung, suggesting the two mechanisms cause PH in Prkg1^−/− mice. The increased pulmonary artery pressure was independent of left-sided heart disease and systemic hypertension at day 45 in Prkg1^−/− mice. Furthermore, the western blot of Prkg1^−/− mice showed decreased phosphorylation of Rho A Ser188 and increased activation of Rho A. After fasudil (a Rho kinase inhibitor) treatment, a significant decrease in pulmonary artery pressure was noted in Prkg1^−/− mice.

In this study, the authors showed that PKG-1 deficiency results in activation of Rho A-Rho kinase signalling, which causes vascular remodelling and vasoconstriction, leading to PH. Short term inhibition of Rho kinase by fasudil decreased pulmonary pressure in Prkg1^−/− mice. Thus, based on the mouse model, PKG-1 deficiency should be one of the important key mechanisms inducing pulmonary artery pressure in Prkg1^−/− mice. However, extrapolating this evidence from Prkg1^−/− mice to PH human population will require further study.

▸ Zhao YD, Cai L, Mirza MK, et al. Protein Kinase G-1 deficiency induces pulmonary hypertension through Rho A/Rho kinase activation. Am J Pathol 2012 Jun 180(6); 2268–75.