E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.

Autor:	Yi D; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix.; Translational Cardiovascular Research Center (D.Y., B.L., W.H.L., C.C.G., Z.D.), University of Arizona, Phoenix., Liu B; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix.; Translational Cardiovascular Research Center (D.Y., B.L., W.H.L., C.C.G., Z.D.), University of Arizona, Phoenix., Ding H; College of Medicine-Phoenix, Department of Pharmacy Practice & Science, College of Pharmacy (H.D.)., Li S; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Li R; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Pan J; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Ramirez K; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Xia X; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Kala M; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Ye Q; Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus (Q.Y., Y.Z.)., Lee WH; Translational Cardiovascular Research Center (D.Y., B.L., W.H.L., C.C.G., Z.D.), University of Arizona, Phoenix.; Department of Basic Medical Sciences (W.H.L.), University of Arizona, Phoenix., Frye RE; Rossignol Medical Center, Phoenix, AZ (R.E.F.)., Wang T; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix.; Department of Environmental Health Science and Center of Translational Science, Florida International University, Port Saint Lucie (T.W.)., Zhao Y; Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus (Q.Y., Y.Z.)., Knox KS; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Glembotski CC; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix.; Translational Cardiovascular Research Center (D.Y., B.L., W.H.L., C.C.G., Z.D.), University of Arizona, Phoenix., Fallon MB; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix., Dai Z; Division of Pulmonary, Critical Care and Sleep (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., K.S.K., Z.D.), University of Arizona, Phoenix.; Department of Internal Medicine (D.Y., B.L., S.L., R.L., J.P., K.R., X.X., M.K., T.W., K.S.K., C.C.G., M.B.F., Z.D.), University of Arizona, Phoenix.; Translational Cardiovascular Research Center (D.Y., B.L., W.H.L., C.C.G., Z.D.), University of Arizona, Phoenix.; BIO5 Institute (Z.D.), University of Arizona, Phoenix.; Sarver Heart Center (Z.D.), University of Arizona, Phoenix.
Jazyk:	angličtina
Zdroj:	Hypertension (Dallas, Tex. : 1979) [Hypertension] 2023 Nov; Vol. 80 (11), pp. 2357-2371. Date of Electronic Publication: 2023 Sep 22.
DOI:	10.1161/HYPERTENSIONAHA.123.21241
Abstrakt:	Background: Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported. Methods: SOX17 expression was evaluated in the lungs and pulmonary endothelial cells (ECs) of patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion were generated to determine the role of SOX17 deficiency in the pathogenesis of PAH. Human pulmonary ECs were cultured to understand the role of SOX17 deficiency. Single-cell RNA sequencing, RNA-sequencing analysis, and luciferase assay were performed to understand the underlying molecular mechanisms of SOX17 deficiency-induced PAH. E2F1 (E2F transcription factor 1) inhibitor HLM006474 was used in EC-specific Sox17 mice. Results: SOX17 expression was downregulated in the lung and pulmonary ECs from patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion induced spontaneously mild pulmonary hypertension. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced pulmonary hypertension in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and antiapoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP (bone morphogenetic protein) signaling. E2F1 signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction. Pharmacological inhibition of E2F1 in Sox17 EC-deficient mice attenuated pulmonary hypertension development. Conclusions: Our study demonstrated that endothelial SOX17 deficiency induces pulmonary hypertension through E2F1. Thus, targeting E2F1 signaling represents a promising approach in patients with PAH. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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