Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators
Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators
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DOI：
10.1007/s00210-004-0980-z
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发表时间：
2004-10-01
影响因子：
3.6
通讯作者：
Douglas, SA
中科院分区：
文献类型：
--
作者：
Johns, DG;Ao, ZH;Douglas, SA
尿加压素-II（U-II）是目前发现的最强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。心肌细胞肥大是导致心肌质量增加的主要原因。神经体液因子如血管紧张素-II、内皮素-1、儿茶酚胺和炎性细胞因子被认为介导这种反应。U-II与其他肥大G（q）偶联受体配体（例如血管紧张素II和内皮素-1）具有相似的生物活性，但U-II在心肌细胞肥大中的作用尚未得到表征。本研究的假设是，U-II通过其G（q）偶联受体UT发挥作用，在心肌肥厚性重塑中发挥肥厚作用。我们报道了腺病毒上调UT受体“暴露”了H9 c2心肌细胞中U-II诱导的肥大，其阈值反应为202 +/- 8个结合位点/细胞。通过报告基因测定（EC 50 0.7 +/- 0.2 nM）和[H-3]-亮氨酸掺入（EC 50 150 +/- 40 nM）测定，U-II在诱导肥大方面与苯丙氨酸同样有效。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在心肌细胞中比凋亡或增生更肥大。U-II（10 nM）刺激表达UT的心肌细胞释放白细胞介素-6（6 h时为4.6倍）。最后，在大鼠心力衰竭模型中，心肌损伤后心室U-II、UT受体、白细胞介素-6和白细胞介素-1-β的mRNA表达呈时间依赖性增加。这些结果表明，U-II可能通过UT刺激心肌细胞肥大和上调炎性细胞因子在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管理的新治疗靶点。
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 (EC50 0.7 +/- 0.2 nM) and [H-3]-leucine incorporation (EC50 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.