Molecular and Clinical Study of Cardiovascular Hormones

最近的研究表明，新的“心血管激素”可能与高血压和心肌梗死等各种心血管疾病有关。为了进一步探讨它们的作用，我们在包括基因工程动物模型在内的临床和实验环境中从分子水平上研究了利钠肽系统、内皮素系统和肾素-血管紧张素系统。具有血管松弛和抗增殖特性的C型利钠肽(CNP)在与血管平滑肌细胞(VSVC)共同培养时，通过转化生长因子-β(TGF-β)的激活而显著增加，而被血管内皮生长因子或胰岛素显著抑制。此外，腺病毒介导的cnp基因转移可诱导血管内皮细胞G1期停滞，cnp诱导抗增殖的同源异型盒Gax，而不是血管紧张素II的作用。因此，这些多个介质可能在血管重塑中局部相互作用，成为ca…的潜在靶点。更多的是排卵基因疗法。我们还发现，过度表达脑利钠肽(BNP)的转基因小鼠表现出显著的低血压和心脏重量减少，表明其心脏保护作用。我们进一步揭示了BNP和ANP基因在小鼠和人子宫中的串联组织。我们还通过RNA选择性剪接揭示了内皮素-A受体在人类各种组织中的存在，表明其在基因表达中具有调节作用。血管紧张素II 2型(AT_2)受体在人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。在培养的大鼠肾小球系膜细胞中，AT_2受体在融合时被显著诱导，并发挥抗增殖作用，拮抗AT_1受体。AT2受体在遗传性高血压大鼠肾脏中的低表达提示其在高血压发病机制中的作用。此外，在过度表达小鼠肾素(REN-2)的高血压转基因大鼠中，心脏刺激时ANP和BNP的分泌减少，表明其在心血管并发症中起到了作用。较少

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