Abstract

This is a proposal to examine the physiologic contributions of K channels in pulmonary vascular smooth towards their response to hypoxia. The central hypotheses are that both acute and chronic hypoxia inhibit K channels at a functional or transcriptional level, respectively. Inhibition of these channels results in Em (membrane potential) depolarization and opening of voltage gated Ca channels initiating hypoxic vasoconstriction.
The aims are: 1) characterize electrophysiological properties of K channels and determine the molecular basis of native IK(V) in pulmonary artery smooth muscle cells (PASMC); 2) identify Kv channel alpha subunits that determine whole cell IK(V) and regulate Em; 3) specify Kv channels that are sensitive to hypoxia and define the mechanism of hypoxic mediated inhibition; and 4) examine effects of chronic hypoxia on function and expression of Kv channels in PASMC.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054043-07
Application #
6389457
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Garfinkel, Susan J
Project Start
1995-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
7
Fiscal Year
2001
Total Cost
$303,750
Indirect Cost

  Institution

Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Song, Michael Y; Makino, Ayako; Yuan, Jason X-J (2011) Role of reactive oxygen species and redox in regulating the function of transient receptor potential channels. Antioxid Redox Signal 15:1549-65
Kuang, Tuguang; Wang, Jun; Pang, Baosen et al. (2010) Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats. Pulm Pharmacol Ther 23:456-64
Burg, Elyssa D; Platoshyn, Oleksandr; Tsigelny, Igor F et al. (2010) Tetramerization domain mutations in KCNA5 affect channel kinetics and cause abnormal trafficking patterns. Am J Physiol Cell Physiol 298:C496-509
Ogawa, Aiko; Firth, Amy L; Yao, Weijuan et al. (2009) Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 297:L666-76
Yao, Weijuan; Firth, Amy L; Sacks, Richard S et al. (2009) Identification of putative endothelial progenitor cells (CD34+CD133+Flk-1+) in endarterectomized tissue of patients with chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 296:L870-8
Firth, Amy L; Yau, Jocelyn; White, Amanda et al. (2009) Chronic exposure to fibrin and fibrinogen differentially regulates intracellular Ca2+ in human pulmonary arterial smooth muscle and endothelial cells. Am J Physiol Lung Cell Mol Physiol 296:L979-86
Firth, Amy L; Platoshyn, Oleksandr; Brevnova, Elena E et al. (2009) Hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells. Ann N Y Acad Sci 1177:101-11
Yu, Ying; Keller, Steve H; Remillard, Carmelle V et al. (2009) A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119:2313-22
Firth, Amy L; Remillard, Carmelle V; Yuan, Jason X-J (2007) TRP channels in hypertension. Biochim Biophys Acta 1772:895-906
Mauban, Joseph R H; Wilkinson, Katherine; Schach, Christian et al. (2006) Histamine-mediated increases in cytosolic [Ca2+] involve different mechanisms in human pulmonary artery smooth muscle and endothelial cells. Am J Physiol Cell Physiol 290:C325-36

Showing the most recent 10 out of 12 publications