Oxidant Signaling in Pulmonary Hypertension

点击翻译按钮获取中文摘要

PROJECT SUMMARY Pulmonary vascular dysfunction resulting from chronic hypoxia (CH) leads to increased vascular resistance and resultant pulmonary hypertension (PH) in patients with chronic obstructive pulmonary diseases, sleep ap- nea, restrictive lung diseases, and in residents at high altitude. The resulting increase in afterload on the right heart often leads to clinical manifestations of cor pulmonale, peripheral edema, morbidity and mortality. Alt- hough it is widely considered that pulmonary arterial constriction and remodeling are central to this disease process, the mechanisms linking CH to these responses are poorly understood. The overall objective of the current study is to identify oxidant signaling mechanisms responsible for spon- taneous pulmonary arterial smooth muscle cell (PASMC) tone and enhanced vasoconstrictor reactivity in CH- induced PH. Based on preliminary data, our central hypothesis is that PASMC Cav1 dysfunction following CH disrupts cellular cholesterol homeostasis that confers transduction of mechanical, electrical and GPCR stimuli to mitochondrial Ca2+ uniporter (MCU)-dependent mitochondrial reactive oxygen species (mtROS) generation, vasoconstriction, and pHTN. We plan to test this hypothesis by pursuing the following specific aims: Specific Aim #1: Establish the mechanism by which CH reduces PASMC membrane cholesterol leading to enhanced vasoconstrictor reactivity and cell proliferation. Hypothesis: CH couples vasoconstrictor stimuli to PASMC myofilament Ca2+ sensitization and proliferation through impaired Cav1-mediated cholesterol trafficking to the cell membrane. Specific Aim #2: Define the signaling mechanism by which CH increases PASMC mtROS generation, vaso- constriction, and cell proliferation. Hypothesis: Cav1 dysfunction following CH causes mitochondrial membrane cholesterol accumulation and MCU-dependent mtROS generation required for augmented PASMC contractility and proliferation. Specific Aim #3: Determine the contribution of Cav1, MCU and mtROS to CH-induced pHTN. Hypothesis: Cav1 dysregulation and MCU-induced mtROS production contribute to the progression and maintenance of CH-induced pHTN. We anticipate this project will define an innovative paradigm of PASMC signaling involving regulation of mtROS generation and Ca2+ sensitization by Cav1-mediated disruption of cellular cholesterol homeostasis that is unique to the pulmonary circulation. The proposed studies are significant because they are expected to ver- tically impact our understanding of regulation of oxidant signaling mechanisms by Cav1 and membrane cho- lesterol, and their contribution to CH-induced pHTN. In doing so, they have potential to provide new thera- peutic strategies to treat pHTN that target components of this signaling pathway.