Department of Molecular Cardiology, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA.
Hypertension. 2012 Nov;60(5):1352-8. doi: 10.1161/HYPERTENSIONAHA.112.201244. Epub 2012 Sep 17.
Blacks represent a high-risk population for salt-sensitive hypertension and heart disease, but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in blacks with hypertension and cardiac hypertrophy. In this study, we tested the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were generated to express wild-type (WT) or T555I/Q568P variant corin in the heart under the control of α-myosin heavy chain promoter. The mice were crossed into a corin knockout (KO) background to create KO/TgWT and KO/TgV mice that expressed WT or variant corin, respectively, in the heart. Functional studies showed that KO/TgV mice had significantly higher levels of proatrial natriuretic peptide in the heart compared with that in control KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. By radiotelemetry, corin KO/TgV mice were found to have hypertension that was sensitive to dietary salt loading. The mice also developed cardiac hypertrophy at 12 to 14 months of age when fed a normal salt diet or at a younger age when fed a high-salt diet. The phenotype of salt-sensitive hypertension and cardiac hypertrophy in KO/TgV mice closely resembles the pathological findings in blacks who carry the corin variant. The results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in blacks.
黑人代表了盐敏感性高血压和心脏病的高危人群，但潜在的机制仍不清楚。Corin 是一种心脏蛋白水解酶，通过激活利钠肽来调节血压。在患有高血压和心脏肥大的黑人群体中发现了 Corin 基因变异（T555I/Q568P）。在这项研究中，我们检验了 Corin 变异体在体内导致高血压和心脏肥大表型的假说。通过α肌球蛋白重链启动子在心脏中表达野生型（WT）或 T555I/Q568P 变异 Corin，生成了转基因小鼠。将这些小鼠与 Corin 敲除（KO）背景杂交，创建了分别在心脏中表达 WT 或变异 Corin 的 KO/TgWT 和 KO/TgV 小鼠。功能研究表明，与对照 KO/TgWT 小鼠相比，KO/TgV 小鼠心脏中的前心房利钠肽水平显著升高，这表明 Corin 变异体在体内处理利钠肽的功能有缺陷。通过无线电遥测，发现 Corin KO/TgV 小鼠患有高血压，对饮食盐负荷敏感。当给予正常盐饮食时，这些小鼠在 12 至 14 个月时会发生心脏肥大，而在给予高盐饮食时，会在更年轻时发生心脏肥大。KO/TgV 小鼠的盐敏感性高血压和心脏肥大表型与携带 Corin 变异体的黑人的病理发现非常相似。结果表明，Corin 缺陷可能代表黑人盐敏感性高血压和心脏肥大的重要机制。
