Pulmonary vascular medial hypertrophy in patients with primary pulmonary hypertension (PPH) is mainly due to increased pulmonary artery smooth muscle cell (PASMC) growth and/or decreased PASMC apoptosis. The precise control of the balance between PASMC proliferation and apoptosis plays a critical role in maintaining the structural integrity of the pulmonary vasculature. Activation of apoptosis is implicated in the regression of pulmonary vascular medial hypertrophy, whereas inhibition of apoptosis leads to the progression of pulmonary vascular wall thickening. Cell volume decrease is an early hallmark of apoptosis. Maintenance of a high concentration of cytosolic K+ ([K+]cyt) is essential to the regulation of normal ion homeostasis and cell volume, and to the suppression of cytoplasmic caspases. Thus, activation of K+ channels induces apoptotic volume decrease (AVD) and apoptosis by enhancing K +loss, whereas inhibition of K+ channel activity attenuates AVD by maintaining sufficient [K+]cyt to inhibit apoptosis. ? ? In normal PASMC, our preliminary data demonstrate that apoptosis inducers, such as staurosporine (ST) and cytochrome c, increased K+ channel activity, whereas anti-apoptotic proteins (e.g., Bcl-2) decreased K+ channel activity. Pharmacological blockade of voltage-gated K+(Kv) channels attenuated ST-induced apoptosis. Furthermore, expression and function of Kv channels were markedly reduced in PASMC from PPH patients in comparison to PASMC from normal subjects and patients with secondary pulmonary hypertension (SPH). The ST-induced apoptosis was also significantly inhibited in PPH-PASMC in comparison to SPH-PASMC. Based on these data, we hypothesize that inhibition of apoptosis in PASMC as a result of down regulation and dysfunction of Kv channels plays an critical role in the development of pulmonary vascular medial hypertrophy in PPH.
Three Specific Aims are addressed to test the hypothesis: 1) To investigate the role of Kv channels in the development of AVD and apoptosis and to identify Kv channel subtypes that are involved in regulating cell volume in normal human PASMC; 2) To determine the effects of pro-apoptotic and anti-apoptotic proteins on Kv channel expression and function in human PASMC; and 3) To determine whether apoptosis is inhibited in PPH-PASMC and if so, what cellular and molecular mechanisms are responsible for the inhibited apoptosis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064945-06
Application #
6765271
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (03))
Program Officer
Denholm, Elizabeth M
Project Start
1999-07-15
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$380,000
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Firth, Amy L; Mandel, Jess; Yuan, Jason X-J (2010) Idiopathic pulmonary arterial hypertension. Dis Model Mech 3:268-73
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
Firth, Amy L; Yao, Weijuan; Remillard, Carmelle V et al. (2010) Upregulation of Oct-4 isoforms in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 298:L548-57
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
Sacks, Richard S; Firth, Amy L; Remillard, Carmelle V et al. (2008) Thrombin-mediated increases in cytosolic [Ca2+] involve different mechanisms in human pulmonary artery smooth muscle and endothelial cells. Am J Physiol Lung Cell Mol Physiol 295:L1048-55
Firth, Amy L; Yuan, Jason X-J (2008) Bringing down the ROS: a new therapeutic approach for PPHN. Am J Physiol Lung Cell Mol Physiol 295:L976-8
Ogawa, Aiko; Firth, Amy L; Yao, Weijuan et al. (2008) Prednisolone inhibits PDGF-induced nuclear translocation of NF-kappaB in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 295:L648-57
Rao, Jaladanki N; Liu, Stephen V; Zou, Tongtong et al. (2008) Rac1 promotes intestinal epithelial restitution by increasing Ca2+ influx through interaction with phospholipase C-(gamma)1 after wounding. Am J Physiol Cell Physiol 295:C1499-509

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