Molecular and Clinical Study of Cardiovascular Hormones

最近的研究表明，新的“心血管激素”可能涉及各种心血管疾病，如高血压和心肌梗死。为了进一步探索它们的作用，我们在临床和实验环境（包括基因工程动物模型）中从分子水平研究了利钠肽系统、内皮素系统和肾素-血管紧张素系统。具有血管舒张和抗增殖特性的C型利钠肽（CNP）的内皮产生在与血管平滑肌细胞（VSVC）共培养下通过TGF-β激活而显著增加，血管内皮生长因子或胰岛素显著降低。此外，腺病毒介导的CNP基因转移到VSMC中可诱导G1期阻滞，CNP诱导抗增殖同源框Gax，而不是血管紧张素II的作用。因此，这些多种介质可能在血管重塑中局部相互作用，成为血管重塑的潜在靶点。 关于我们 体外基因治疗我们还发现，过表达脑钠肽（BNP）的转基因小鼠表现出显着的低血压，心脏质量减少，表明其心脏保护作用。我们进一步揭示了BNP和ANP基因在小鼠和人类基因组中是串联的。我们还通过选择性RNA剪接揭示了内皮素A受体在各种人类组织中的存在，提示其基因表达的调节作用。血管紧张素II 2型（AT_2）受体在人类子宫肌层中大量表达，并在妊娠期间显著下调，提示其在子宫功能中的作用。在培养的大鼠系膜细胞中，AT_2受体在汇合时被显著诱导，并发挥抗增殖作用，对抗AT_1受体。AT_2受体在遗传性高血压大鼠肾脏中的低表达提示其参与了高血压的发病机制。此外，在高血压转基因大鼠过表达小鼠肾素（Ren-2），心分泌的ANP和BNP刺激后减弱，这表明其贡献的心血管并发症。少

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 … More 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