title: Down-regulation of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor by HEXIM1 attenuates myocardial angiogenesis in hypoxic mice.
abstract: Pulmonary hypertension (PH) sustains elevation of pulmonary vascular resistance and ultimately leads to right ventricular (RV) hypertrophy and failure and death. Recently, proangiogenic factors hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) have been known to promote left ventricular myocardial angiogenesis and lead to cardiac hypertrophy, and this would be involved in RV hypertrophy of PH patients. Previously, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice ameliorates RV hypertrophy in hypoxia-induced PH model. Given these results, here we analyzed the effect of HEXIM1 on the expression of HIF-1α and VEGF and on myocardial angiogenesis of RV in PH. We revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of HIF-1α protein and its target genes including VEGF in the cultured cardiac myocytes and fibroblasts, and that cardiomyocyte-specific HEXIM1 transgenic mice repressed RV myocardial angiogenesis in hypoxia-induced PH model. Thus, we conclude that HEXIM1 could prevent RV hypertrophy, at least in part, via suppression of myocardial angiogenesis through down-regulation of HIF-1α and VEGF in the myocardium under hypoxic condition.
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: n-yoshi@ims.u-tokyo.ac.jp.
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hosono
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Division of Rheumatology, Center for Antibody and Vaccine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000254:growth & development*; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; C118642:Hexim1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Cardiac hypertrophy; HEXIM1; HIF-1α; Pulmonary hypertension; VEGF