The present proposal seeks to address the molecular regulation of the calcium-sensitive potassium (BKCa) channel, an ion channel that is ubiquitously expressed in smooth muscle cells (SMC) and determines, to a meaningful degree, vascular SMC tone. Prior work from our lab has demonstrated a developmentally regulated and biologically imperative role for the BKCa channel in pulmonary artery (PA) SMC, as physiologic stimuli such as an acute increase in oxygenation, ventilation, and nitric oxide cause perinatal pulmonary vasodilation, at least in part, through activation of the BKCa channel. The gating characteristics of the channel are modified by several subunits, with the most widely expressed, the ?1 subunit, enhancing calcium sensitivity of the channel and thereby dampening the response to constrictor stimuli. ?1 subunit expression has physiologic implications as gain-of-function polymorphisms in the KCNMB1 gene protect against diastolic hypertension, and absence of the ?1 subunit in mice causes hypertension. The subunit likely has implications for airways reactivity as a specific polymorphism in African Americans increases the risk for severe asthma. How ?1 subunit expression is regulated and whether it plays a role in determining pulmonary vascular tone remains unexplored. Based on compelling preliminary evidence demonstrating that hypoxia induces an increase in ?1 expression that is mediated by hypoxia-inducible factor-1? in PASMC, we formulated the overall hypothesis that in PASMC: (i) the capacity for hypoxia to increase KCNMB1 expression;and (ii) normoxic KCNMB1 expression, are developmentally regulated. In three closely related specific aims, we seek to rigorously test the working hypothesis by demonstrating in Aim 1 that loss of the ?1 subunit accentuates hypoxic pulmonary hypertension in a murine model.
In Aim 2, we plan to elucidate the transcriptional regulation that accounts for the hypoxic induction of KCNMB1. Finally, in Aim 3, we plan to address the potential that either epigenetic factors or specific micro-RNA molecules constrain KCNMB1 expression with aging. The studies to be performed will clearly establish the importance of ?1 subunit in the regulation of pulmonary vascular tone and hold the promise of providing a novel target that might be exploited to address diseases wherein pulmonary vascular, or potentially even airway, SMC tone is pathologically increased.
The mass and contractile state of muscle cells that encircle the blood vessels of the lungs are increased in diseases wherein the blood pressure of the lungs is elevated. If these cells do not relax properly following the birth of infants, life-threatning illness results. The present application endeavors to identify a new strategy to decrease the tone in these cells, an approach that may be more broadly applicable to diseases such as asthma and high pressure.
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