Vascular smooth muscle cell phenotypic switching in Pulmonary Hypertension

描述（由申请人提供）：肺动脉高压（Pulmonary Hypertension， PH）是一种高死亡率的严重疾病。肺血管重塑是PH发病的关键，目前的治疗方法并不能有效地靶向这种疾病的固定组成部分。常驻肺血管平滑肌细胞（VSMCs）从收缩型表型转变为合成/增殖型，主要是糖酵解型表型，这有助于PH下肺血管重塑，并可能是对血管扩张剂反应性差的基础。然而，VSMC表型转换是一个可逆的过程，因此是一个有前景的研究领域，可能会导致新的治疗方法，逆转已建立的重塑和增强对肺血管扩张剂的反应性。因此，了解VSMC分化途径在PH发病机制及其逆转中的作用对于确定这种新的治疗分子靶点至关重要。我们的初步数据支持carg -心肌素(MyoC)-血清反应因子（SRF）转录复合物是VSMC分化的主要调节因子，参与了PH的发病机制，可以作为治疗靶点。此外，通过使用两种PH实验模型，我们发现一种新的干预措施，即使用NH4Cl治疗诱导轻度代谢性酸中毒，可以预防PH，逆转已建立的重塑并改善对肺血管扩张剂的反应性。本研究的主要目的是：(i)确定carg -心肌素-血清反应因子（SRF）转录复合物在PH发病机制及其逆转中的作用；（ii）研究乙酰唑胺诱导临床可行的酸中毒是否会恢复实验性PH中功能性收缩的肺VSMC表型，并改善肺血管对血管扩张剂的反应性。我们的中心假设是carg - mmc - srf转录复合体参与了PH的发病机制，酸中毒通过这一途径恢复功能性收缩的VSMC表型，从而逆转病理性肺血管重塑。我们的具体目标是：(1)确定CArG-MyoC- SRF转录复合物在实验ph的发展和逆转中的作用。(2)。为了验证EA通过carg - mmc - srf转录复合体调节肺VSMC表型转换的假设。（3). 为了验证乙酰唑胺（Acetazolamide， ACTZ）在体内诱导临床可行的代谢性酸中毒（代谢性酸中毒）促进实验性PH下肺VSMC收缩表型的假设。我们的研究旨在确定carg - myc - srf通路中用于PH治疗干预的新分子靶点。

DESCRIPTION (provided by applicant): Pulmonary Hypertension (PH) is a serious disease associated with high mortality. Pulmonary vascular remodeling is key to PH pathogenesis and this fixed component of the disease is not effectively targeted by current therapies. Phenotypic switching of resident pulmonary vascular smooth muscle cells (VSMCs) from a contractile to a synthetic/proliferative and predominantly glycolytic phenotype contributes to pulmonary vascular remodeling in PH and likely underlies poor responsiveness to vasodilators. However, VSMC phenotypic switching is a reversible process and therefore a promising area of investigation that may lead to novel therapies that will reverse established remodeling and enhance responsiveness to pulmonary vasodilators. Understanding the role of VSMC differentiation pathways in PH pathogenesis and its reversal is thus of critical importance in identifying such novel therapeutic molecular targets. Our preliminary data support that the CArG-myocardin (MyoC)-Serum Response Factor (SRF) transcriptional complex, a master regulator of VSMC differentiation, is involved in PH pathogenesis and can be therapeutically targeted. In addition, using two experimental models of PH, we discovered that a novel intervention, using induction of mild metabolic acidosis with NH4Cl treatment, leads to prevention of PH, reversal of established remodeling and improved responsiveness to pulmonary vasodilators. The primary objectives of this proposal are (i) to define the role of the CArG-myocardin-Serum Response Factor (SRF) transcriptional complex in PH pathogenesis and its reversal (ii) to examine whether induction of clinically feasible acidosis with the use of Acetazolamide will restore a functionally contractile pulmonary VSMC phenotype in experimental PH and improve pulmonary vascular responsiveness to vasodilators. Our central hypothesis is that the CArG-MyoC-SRF transcriptional complex is involved in PH pathogenesis and that acidosis reverses pathologic pulmonary vascular remodeling by restoring a functionally contractile VSMC phenotype via this pathway. Our specific aims are: (1) To define the role of the CArG-MyoC- SRF transcriptional complex in the development and reversal of experimental PH. (2). To test the hypothesis that EA modulates pulmonary VSMC phenotype switching via the CArG-MyoC-SRF transcriptional complex. (3). To test the hypothesis that in vivo induction of clinically feasible metabolic acidoss with Acetazolamide (ACTZ) promotes a contractile pulmonary VSMC phenotype in experimental PH. Our studies are designed to identify novel molecular targets in the CArG-MyoC-SRF pathway for therapeutic interventions for PH.