Epigenetic regulation of pulmonary smooth muscle cell remodeling in Pulmonary Hypertension

Indiana University Indianapolis, Indianapolis IN

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Abstract

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. .