Epigenetic regulation of pulmonary smooth muscle cell remodeling in Pulmonary Hypertension

进展性和终末性肺动脉高压(PH)的定义是近端肺闭塞 血管，远端微血管丧失，以及右心衰竭。尽管有病理性的血管壁增厚 而重塑是PH发病率的重要原因，目前的治疗目标是对症缓解 血管收缩和心力衰竭。虽然最近的研究表明，异常的内皮和平滑肌 细胞基因转录参与肺动脉高压血管重塑，表观遗传调节因子介导这一过程 人们对此了解甚少。在其他疾病过程中，鞘氨醇激酶(SPHK)2/鞘氨醇1- 磷酸(S1P)轴是一种强大的表观遗传调节因子。然而，在PH中，SPHK2的表观遗传学作用 在很大程度上被忽视了。一种功能不同的鞘氨酸激酶同工酶SPHK2催化 核鞘氨醇的磷酸化，产生S1P，释放转录共抑制物复合体 激活潜伏的基因转录。我们在人类肺组织中的初步发现发现， 通过组蛋白H3K9(Ac-H3K9)的乙酰化，SPHK2蛋白和改变的乙酰体增加了20倍 一个活跃的染色质标记。此外，在人肺动脉平滑肌细胞(HPASMC)中，SPHK2 调节H3K9的超乙酰化并促进已知的调节茎和 扩散。我们的长期目标是开发不受控制的远端肺血管闭塞的抑制剂。 可用于高血压的临床治疗。此应用程序的总体目标是下一个 实现我们长期目标的步骤是：(I)阐明表观遗传学的分子机制(S)和 激活SPHK2的因子在体外促进PH血管重塑和(II)决定体内 药理SPHK2抑制剂的疗效。我们的中心假设是激活的SPHK2促进远端 通过表观遗传修饰导致肺血管闭塞的肺血管重塑。 这一假设是基于使用人类PH组织产生的初步数据和 HPASMC体外和体内缺氧PH啮齿动物模型。在完成建议的研究后，我们的 预期结果是已经确定了SPHK2调节PH肺血管的机制 改建。这些结果预计将产生重要的积极影响，因为它们将提供 SPHK2抑制剂开发的强有力的循证原则证明，最终提供了新的 发展新的PH疗法的机会。 。

Progressive and terminal, pulmonary hypertension (PH) is defined by obliteration of proximal pulmonary vessels, loss of distal microvasculature, and right sided heart failure. Despite pathologic vessel wall thickening and remodeling being a significant cause of PH morbidity, current therapy targets symptomatic relief of vasoconstriction and heart failure. While recent studies suggest that aberrant endothelial and smooth muscle cell gene transcription contributes to PH vascular remodeling, epigenetic regulators that mediate this process are poorly understood. In other disease processes, the sphingosine kinase (SPHK) 2 / sphingosine 1- phosphate (S1P) axis is a powerful epigenetic regulator. However, in PH the epigenetic role of SPHK2 has been largely overlooked. A functionally distinct sphingosine kinase isoenzyme, SPHK2 catalyzes phosphorylation of nuclear sphingosine, generating S1P, that unleashes transcription co-repressor complexes to activate latent gene transcription. Our preliminary findings in human PH lung tissues identified a significant 20-fold increase in SPHK2 protein and an altered acetylome via acetylation of histone H3K9 (Ac-H3K9) that is an active chromatin mark. Moreover, in human pulmonary artery smooth muscle cells (hPASMC) SPHK2 regulated hyperacetylation of H3K9 and promoted transcription of genes known to regulate stemness and proliferation. Our long-term goal is to develop inhibitors for uncontrolled obliteration of distal pulmonary vessels that can be used for the clinical treatment of PH. Our overall objectives for this application, which are the next steps toward attainment of our long-term goal, are to (i) elucidate the epigenetic molecular mechanism(s) and factors activating SPHK2 that contribute to PH vascular remodeling in vitro and (ii) determine the in vivo efficacy of pharmacologic SPHK2 inhibitors. Our central hypothesis is that activated SPHK2 promotes distal pulmonary vascular remodeling through epigenetic modifications that contribute to PH vascular obliteration. This hypothesis has been formulated based on preliminary data generated using human PH tissue and hPASMC in vitro, and in vivo hypoxia PH rodent models. At the completion of the proposed research, our expected outcomes are to have defined the mechanisms by which SPHK2 regulates PH pulmonary vascular remodeling. These results are expected to have an important positive impact because they will provide a strong evidence-based proof of principle for development of SPHK2 inhibitors, ultimately providing new opportunities for development of novel PH therapies. .