Johns Douglas G, Ao Zhaohui, Naselsky Diane, Herold Christopher L, Maniscalco Kristeen, Sarov-Blat Lea, Steplewski Klaudia, Aiyar Nambi, Douglas Stephen A
Department of Vascular Biology and Thrombosis, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, UW2510, King of Prussia, PA 19406, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2004 Oct;370(4):238-50. doi: 10.1007/s00210-004-0980-z. Epub 2004 Sep 30.
Urotensin-II (U-II), the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic G(q)-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its G(q)-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor "unmasked" U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202+/-8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC(50) 0.7+/-0.2 nM) and [(3)H]-leucine incorporation (EC(50) 150+/-40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy ( K(B) 34+/-6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1-beta is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure.
尾加压素 II（U-II）是已确定的最有效的哺乳动物血管收缩剂，其受体 UT 在充血性心力衰竭（CHF）患者的心脏组织和血浆中表达增加。心肌细胞肥大是与心脏损伤相关的心肌质量增加的主要原因。血管紧张素 II、内皮素-1、儿茶酚胺和炎性细胞因子等神经体液因子被认为介导了这种反应。U-II 与血管紧张素 II 和内皮素-1 等其他肥大性 G(q) 偶联受体配体具有相似的生物学活性，但 U-II 在心肌细胞肥大中的作用尚未明确。本研究的假设是，U-II 通过其 G(q) 偶联受体 UT 在心脏肥大重塑中发挥肥大作用。我们报告，腺病毒介导的 UT 受体上调在 H9c2 心肌细胞中“揭示”了 U-II 诱导的肥大，阈值反应为 202±8 个结合位点/细胞。通过报告基因检测（EC(50) 0.7±0.2 nM）和[³H]-亮氨酸掺入（EC(50) 150±40 nM）测量，U-II 在诱导肥大方面与去氧肾上腺素同样有效。一种竞争性肽类 UT 受体拮抗剂 BIM-23127 可抑制 U-II 诱导的肥大（K(B) 34±6 nM）。U-II 不影响细胞增殖或凋亡，表明 U-II 在心肌细胞中更倾向于引起肥大而非凋亡或增生。U-II（10 nM）刺激表达 UT 的心肌细胞释放白细胞介素-6（6 小时时增加 4.6 倍）。最后，在大鼠心力衰竭模型中，心肌损伤后，心脏心室中 U-II、UT 受体、白细胞介素-6 和白细胞介素-1-β 的 mRNA 表达随时间依赖性增加。这些结果表明，U-II 可能通过 UT 刺激心肌细胞肥大并上调炎性细胞因子，在与 CHF 相关的心脏重塑中发挥作用。因此，UT 拮抗作用可能代表心力衰竭临床治疗的一个新的治疗靶点。
