Role of Rho kinase and Na+/H+ exchange in hypoxia-induced pulmonary arterial smooth muscle cell proliferation and migration.

Abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are hallmark characteristics of vascular remodeling in pulmonary hypertension induced by chronic hypoxia. In this study, we investigated the role of the Na(+)/H(+)exchanger (NHE) and alterations in intracellularpH(pHi) homeostasis in meditating increased proliferation and migration inPASMCs isolated from resistance-sized pulmonary arteries from chronically hypoxic rats or from normoxic rats that were exposed to hypoxia ex vivo (1% or 4% O2, 24-96 h). We found thatPASMCs exposed to either in vivo or ex vivo hypoxia exhibited greater proliferative and migratory capacity, elevated pHi, and enhancedNHEactivity. TheNHEinhibitor, ethyl isopropyl amiloride (EIPA), normalized pHiin hypoxicPASMCs and reduced migration by 73% and 45% in cells exposed to in vivo and in vitro hypoxia, respectively. Similarly,EIPAreduced proliferation by 97% and 78% in cells exposed to in vivo and in vitro hypoxia, respectively. We previously demonstrated thatNHEisoform 1 (NHE1) is the predominant isoform expressed inPASMCs. The development of hypoxia-induced pulmonary hypertension and alterations inPASMC pHihomeostasis were prevented in mice deficient forNHE1. We found that short-term (24 h) ex vivo hypoxic exposure did not alter the expression ofNHE1, so we tested the role of Rho kinase (ROCK) as a possible means of increasingNHEactivity. In the presence of theROCKinhibitor, Y-27632, we found that pHiandNHEactivity were normalized and migration and proliferation were reduced inPASMCs exposed to either in vivo (by 68% for migration and 22% for proliferation) or ex vivo (by 43% for migration and 17% for proliferation) hypoxia. From these results, we conclude that during hypoxia, activation ofROCKenhancesNHEactivity and promotesPASMCmigration and proliferation.

Walker J ，Undem C ，Yun X ，Lade J ，Jiang H ，Shimoda LA ... -  《Physiological Reports》

Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension.

Xu EZ ，Kantores C ，Ivanovska J ，Engelberts D ，Kavanagh BP ，McNamara PJ ，Jankov RP ... -  《-》

Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells.

Rios EJ ，Fallon M ，Wang J ，Shimoda LA ... -  《-》

Attenuation of pulmonary arterial smooth muscle cell proliferation following hypoxic pulmonary hypertension by the Na+/H+ exchange inhibitor amiloride.

Liu Y ，Zhang B ，Dong MQ ，Niu W ，Luo Y ，Gao YQ ，Li ZC ... -  《CHINESE JOURNAL OF PHYSIOLOGY》

Histone demethylase JARID1B regulates proliferation and migration of pulmonary arterial smooth muscle cells in mice with chronic hypoxia-induced pulmonary hypertension via nuclear factor-kappa B (NFkB).

Chronic hypoxia-induced pulmonary hypertension (PH) is a disorder that is characterized by increased pulmonary arterial pressure resulting from lung diseases or shortage of oxygen in the body. Excess proliferation of pulmonary vascular cells such as pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of PH. Recent evidence indicates that, in addition to genetic predisposition and environmental factors, epigenetic mechanisms play a pivotal role in etiology of PH. In this study, we investigated the possible role played by jumonji AT-rich interactive domain 1B (JARID1B), a histone demethylase, in regulating the proliferation of vascular smooth muscle cells in chronic hypoxia-induced PH condition. Quantitative polymerase chain reaction analysis of samples from rats with PH showed an elevated expression of JARID1B in their PASMCs, positively correlating with increased nuclear factor-kappa B (NFkB) expression. Further functional studies in vitro indicated that overexpression of JARID1B increased the proliferation and migration of PASMCs, which were inhibited by depletion of NFkB. Genomewide transcriptional analysis revealed that the JARID1B regulated NFkB signaling pathway by directly binding to its promoter. We have also shown that JARID1B indirectly regulates the expression of vascular endothelial growth factor via NFkB signaling and hence may also play a crucial role in controlling PAECs, leading to changes in vascular architecture in PH. Our findings could lead to further studies on the role of JARID1B in PH etiology and therefore could lead to a potential therapeutic target for chronic hypoxia induced pulmonary hypertension.

Li Y ，Liu S ，Zhang Y ，Gao Q ，Sun W ，Fu L ，Cao J ... -  《-》