Role of Rho kinase and Na+/H+ exchange in hypoxia-induced pulmonary arterial smooth muscle cell proliferation and migration. Physiol Rep 2016 Mar;4(6)
Date
03/25/2016Pubmed ID
27009277Pubmed Central ID
PMC4814889DOI
10.14814/phy2.12702Scopus ID
2-s2.0-84962090048 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
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.
Author List
Walker J, Undem C, Yun X, Lade J, Jiang H, Shimoda LAAuthor
Jasmine Walker MD, MPH Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmidesAmiloride
Animals
Cation Transport Proteins
Cell Hypoxia
Cell Movement
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Enzyme Activation
Hydrogen-Ion Concentration
Hypertension, Pulmonary
Hypoxia
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Protein Kinase Inhibitors
Pulmonary Artery
Pyridines
Rats, Wistar
Signal Transduction
Sodium-Hydrogen Exchanger 1
Sodium-Hydrogen Exchangers
Vascular Remodeling
rho-Associated Kinases
