Prolonged exposure to decreased oxygen tension occurs with many pulmonary diseases, resulting in pulmonary hypertension, significantly worsening prognosis. The cellular mechanisms underlying this process remain poorly understood. Alterations in intracellular pH (pHi) may contribute to regulation of pulmonary arterial smooth muscle cell (PASMC) contraction and growth during chronic hypoxia (CH). Alkaline pHi causes PASMC contraction and is necessary for PASMC proliferation in response to growth factors. Moreover, antagonists of Na+/H+ exchange (NHE) inhibit development of hypoxic pulmonary hypertension. Our data indicate that exposure to CH results in alkalinization of PASMCs and increased NHE activity. This increase in NHE activity could be due to a change in the expression of the exchanger; however, the factors influencing NHE expression are not clear. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates numerous adaptive responses to hypoxia through the regulation of gene induction. We have developed a mouse model of hypoxic pulmonary hypertension, and have found that transgenic mice with partial deficiency for the alpha subunit of HIF-1 exhibit reduced pulmonary hypertension in response to CH. Moreover, the CH-induced alkalinization and activation of NHE activity is reduced in PASMCs from these mice. Regulation of NHE expression by HIF-1 has not been demonstrated, but is possible since the promoter of NHE1 contains a putative HIF-1 binding site. In addition to direct effects of alkaline pHi on PASMC contraction and growth, pHi may also regulate vascular caliber through control of [Ca2+]i, as an increase in intracellular Na+ due to increased NHE activity could alter Ca2+ extrusion through Na+/Ca2+ exchange. We have shown that resting [Ca2+]i is also elevated in PASMCs from CH mice, and that this response was dependent on HIF-I. Based on these considerations, we hypothesize that during CH, hypoxic induction of HIF-1 activates NHE1 transcription, resulting in an increase in NHE1 protein expression and increased Na+/H+ exchange. The increase in NHE activity causes an alkaline shift in pHi, which contributes to the elevation in pulmonary artery pressure by modulating PASMC intracellular Ca2+ concentration, contraction, and growth. We will test this hypothesis using a combination of techniques, including isometric tension recording in arterial segments, molecular biological, electrophysiological and micro fluorescence techniques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073859-04
Application #
7076849
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$279,400
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Suresh, Karthik; Servinsky, Laura; Jiang, Haiyang et al. (2018) Reactive oxygen species induced Ca2+ influx via TRPV4 and microvascular endothelial dysfunction in the SU5416/hypoxia model of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 314:L893-L907
Huetsch, John C; Suresh, Karthik; Shimoda, Larissa A (2018) When higher cholesterol is better: membrane cholesterol loss and endothelial Ca2+ signaling. Am J Physiol Heart Circ Physiol 314:H780-H783
Shimoda, Larissa A (2018) Let's Talk about Sex: A Novel Mechanism by Which Estrogen Receptor ? Limits Hypoxia-Inducible Factor Expression in Pulmonary Endothelial Cells. Am J Respir Cell Mol Biol 59:11-12
Suresh, Karthik; Servinsky, Laura; Reyes, Jose et al. (2017) CD36 mediates H2O2-induced calcium influx in lung microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 312:L143-L153
Suresh, Karthik; Shimoda, Larissa A (2016) Lung Circulation. Compr Physiol 6:897-943
Walker, Jasmine; Undem, Clark; Yun, Xin et al. (2016) Role of Rho kinase and Na+/H+ exchange in hypoxia-induced pulmonary arterial smooth muscle cell proliferation and migration. Physiol Rep 4:
Huetsch, John C; Jiang, Haiyang; Larrain, Carolina et al. (2016) The Na+/H+ exchanger contributes to increased smooth muscle proliferation and migration in a rat model of pulmonary arterial hypertension. Physiol Rep 4:
Suresh, Karthik; Servinsky, Laura; Reyes, Jose et al. (2015) Hydrogen peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4. Am J Physiol Lung Cell Mol Physiol 309:L1467-77
Shimoda, Larissa A; Laurie, Steven S (2014) HIF and pulmonary vascular responses to hypoxia. J Appl Physiol (1985) 116:867-74
Shimoda, Larissa A; Laurie, Steven S (2013) Vascular remodeling in pulmonary hypertension. J Mol Med (Berl) 91:297-309

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