| Co-Investigator(Kenkyū-buntansha) |
INAGAMI Tadashi Vanderbilt University, School of Medicine, Professor, 医学部, 教授
DZAU Victor J Harvard Medical School, Department of Medicine, Chairman, 医学部, 教授
MUKOYAMA Masashi Kyoto Univ., Graduate School of Medicine, Asist.Professor, 医学研究科, 助手 (40270558)
ITOH Hiroshi Kyoto Univ., Graduate School of Medicine, Asist.Professor, 医学研究科, 助手 (40252457)
TANAKA Issei Kyoto Univ., Graduate School of Medicine, Assoc.Professor, 医学研究科, 助教授 (80179738)
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| Research Abstract |
Recent studies have shown that novel' cardiovascular hormones' may be implicated in various cardiovascular disorders such as hypertension and myocardial infarction. To further explore their roles, we studied the natriuretic peptide system, endothelin system, and renin-angiotensin system at the molecular level in clinical and experimental settings, including genetically engineered animal models.
Endothelial production of C-type natriuretic peptide (CNP), possessing vasorelaxant and antiproliferative properties, was markedly increased through TGF-BETA activation under coculture with vascular smooth muscle cells (VSVC), and was significantly decreased by vascular endothelial growth factor or insulin. Furthermore, the G1 arrest was induced by adenovirus-mediated CNP gene transfer into VSMC,and CNP induced an antiproliferative homeobox Gax as opposed to the effect of angiotensinII.Thus, these Multiple mediators may be interacting locally in vascular remodeling, being potential targets for ca
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rdiovacular gene therapy. We also showed that transgenic mice overexpressing brain natriuretic peptide(BNP) exhibited significant hypotension with decreased cardiac mass, suggesting its cardioprotective effect. We further revealed that the BNP and ANP genes are organized in tandem in the mouse and humangenomes.
We also revealed the presence of short nonfunctional forms of the endothelin-A receptor in various human tissues by alternative RNA splicing, suggesting a regulatory role in its gene expression.
Angiotensin II type 2(AT_2) receptor was abundantly expressed in human myometrium and markedly down-regulated during pregnancy, suggesting its role in uterine function. In cultured rat mesangial cells, the AT_2 receptor was markedly induced upon confluency and exerted an antiproliferative effect, counteracting the AT_1 receptor. Lower expression of the AT_2 receptor in genetically hypertensive rat kidneys suggested its implication in pathogenesis of hypertension. Furthermore, in hypertensive transgenic rats overexpressing mouse renin (Ren-2), cardiac secretion of ANP and BNP upon stimulation was attenuated, suggesting its contribution to their cardiovascular complications. Less
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