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.
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.
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