Pulmonary hypertension (PH) is a severely debilitating disease with no cure. Morphometric studies revealed that the development of PH is associated with structural remodeling of the small pulmonary arteries, characterized by thickening of the intimal and medial layers and formation of vaso-occlusive lesions. Resistance to apoptosis in both the endothelial and smooth muscle cells (EC and SMC, respectively) is a primary feature of the remodeling process. Based on new preliminary data, this proposal tests the novel hypothesis that SMC and EC survival during PH is promoted by increased Na+/H+ exchange isoform 1 (NHE1) activity, which limits expression of the ER stress signal, CHOP, and prevents activation of caspases, the final executioners of apoptosis. Moreover, although many NHE1 inhibitors exhibit unwanted side effects, rimeporide has been shown to have an improved safety profile. This proposal will test whether inhibition of NHE1 can re-sensitize ECs and PASMCs to endogenous apoptotic signals, resulting in de-remodeling of the pulmonary vasculature. Thus, the goals of this study are to: 1) identify the mechanism by which NHE1 decreases CHOP in pulmonary vascular ECs and SMCs during PH; 2) determine whether NHE1 activity and/or CHOP expression controls EC and SMC susceptibility to apoptosis; 3) elucidate the role of increased NHE1 activity in regulating caspase activity and 4) evaluate the ability of NHE1 inhibition to increase CHOP and reverse remodeling in PH models.

Public Health Relevance

The experiments in this proposal will explore cellular mechanisms involved in the development of pulmonary arterial hypertension (PAH), a devastating disease with limited treatment options. In particular, we will explore the role of the Na+/H+ exchanger in mediating the smooth muscle and endothelial resistance to cell death that contributes to vascular remodeling during development of pulmonary hypertension. Such information is crucial to advancing treatment and developing new therapeutic options to treat this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL073859-09
Application #
9402360
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2003-07-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
9
Fiscal Year
2017
Total Cost
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
21205
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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