Hv1 in Pulmonary Hypertension

ABSTRACT The development of pulmonary hypertension is associated with oxidative stress, endothelial dysfunction, and pulmonary vascular remodeling. Pulmonary vascular remodeling is involved in proliferation and phenotypic transformation of pulmonary endothelial cells and smooth muscle cells. And endothelial dysfunction influences endothelial cell proliferation, and differentiation, leading to endothelial apoptosis-resistant hyperproliferation underlying the pathogenesis of pulmonary hypertension. The voltage-gated proton channel Hv1 has been shown to promote the production of NADPH oxidase (NOX)-derived reactive oxygen species (ROS) and plays an essential role in the regulation of cell proliferation and apoptosis. Here we discovered that Hv1 was implicated in pulmonary hypertension. The expression of Hv1 was significantly upregulated in the lungs of multiple rodent models of pulmonary hypertension and pulmonary hypertension patients. Moreover, deficiency of Hv1 reduced pulmonary hypertension burden in mouse model of hypoxia-induced pulmonary hypertension. To explore the role of Hv1 in the pathogenesis of pulmonary hypertension, we will apply transgenic mice and complementary in vivo approaches to delineate the contributions of Hv1 to the development of pulmonary hypertension. We plan to examine the molecular mechanisms of Hv1-mediated pulmonary hypertension and determine how Hv1 regulates the progression of pulmonary hypertension. Additionally, the Hv1 blockers will be applied to assess the translational potential of targeting Hv1 for treatment of pulmonary hypertension.