Abstract 13430: Salt-Sensitive Hypertension and Cardiac Hypertrophy in Transgenic Mice Expressing a Corin Variant Identified in African Americans
African Americans represent a high risk population for salt-sensitive hypertension and heart disease but underlying mechanisms remain unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin variant (T555I/Q568P) was found to be associated with hypertension and cardiac hypertrophy in African Americans. In this study, we tested the hypothesis that the corin variant contributes to the hypertensive and hypertrophic phenotype in vivo. We created transgenic (Tg) mice expressing wild-type (WT) or T555I/Q568P variant (V) corin in the heart under the control of α-myosin heavy chain promoter. The Tg mice were crossed into a corin knockout (KO) background to create KO/TgWT and KO/TgV mice expressing WT or variant corin specifically in the heart. Western analysis showed that KO/TgV mice had significantly higher levels of pro-atrial natriuretic peptide in the heart compared with that in KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. Consistently, in heart membrane fractions isolated from KO/TgV mice, corin activity was markedly reduced compared to that from KO/TgWT mice. By radiotelemetry, corin KO/TgV mice were found to have higher blood pressures than those in KO/TgWT mice (systolic 124.5 ± 4.0 vs. 111.8 ± 2.9 mmHg; diastolic 91.2 ± 4.0 vs. 82.8 ± 3.3 mmHg; n=6-8/group; p values <0.01). Hypertension in KO/TgV mice was highly sensitive to dietary salt challenge. The mice also developed cardiac hypertrophy, as indicated by increased left ventricular wall, thicker cardiac muscle fibers and greater ratios of heart weight to body weight or tibia length. The hypertrophic phenotype was exacerbated when the mice were fed high salt diets. In conclusion, Tg mice expressing the corin variant developed salt-sensitive hypertension and cardiac hypertrophy, which were similar to the phenotypes in African Americans carrying the corin variant. The data indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in patients, especially in African Americans.
- © 2012 by American Heart Association, Inc.