Callera, G. E., Antunes, T. T., He, Y., Montezano, A. C., Yogi, A., Savoia, C. and Touyz, R. M. (2016) c-Src inhibition improves cardiovascular function but not remodeling or fibrosis in Ang II-induced hypertension. Hypertension, 68(5), pp. 1179-1190. (doi: 10.1161/HYPERTENSIONAHA.116.07699) (PMID:27620391)
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Abstract
c-Src plays an important role in angiotensin II (Ang II) signaling. Whether this member of the Src family kinases is involved in the development of Ang II–induced hypertension and associated cardiovascular damage in vivo remains unknown. Here, we studied Ang II–infused (400 ng/kg/min) mice in which c-Src was partially deleted (c-Src+/−) and in wild-type (WT, c-Src+/+) mice treated with a c-Src inhibitor (CGP077675; 25 mg/kg/d). Ang II increased blood pressure and induced endothelial dysfunction in WT mice, responses that were ameliorated in c-Src+/− and CGP077675-treated mice. Vascular wall thickness and cross-sectional area were similarly increased by Ang II in WT and c-Src+/− mice. CGP077675 further increased cross-sectional area in hypertensive mice. Cardiac dysfunction (ejection fraction and fractional shortening) in Ang II–infused WT mice was normalized in c-Src+/− mice. Increased oxidative stress (plasma thiobarbituric acid–reactive substances, hydrogen peroxide, and vascular superoxide generation) in Ang II–infused WT mice was attenuated in c-Src–deficient and CGP077675-treated mice. Hyperactivation of vascular c-Src, ERK1/2 (extracellular signal–regulated kinase 1/2), and JNK (c-Jun N-terminal kinase) in hypertensive mice was normalized in CGP077675-treated and c-Src+/− mice. Vascular fibronectin was increased by Ang II in all groups and further augmented by CGP077675. Cardiac fibrosis and inflammation induced by Ang II were amplified in c-Src+/− and CGP-treated mice. Our data indicate that although c-Src downregulation attenuates development of hypertension, improves endothelial and cardiac function, reduces oxidative stress, and normalizes vascular signaling, it has little beneficial effect on fibrosis. These findings suggest a divergent role for c-Src in Ang II–dependent hypertension, where c-Src may be more important in regulating redox-sensitive cardiac and vascular function than fibrosis and remodeling.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Montezano, Dr Augusto and Touyz, Professor Rhian and Savoia, Professor Carmine |
| Authors: | Callera, G. E., Antunes, T. T., He, Y., Montezano, A. C., Yogi, A., Savoia, C., and Touyz, R. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Hypertension |
| Publisher: | American Heart Association |
| ISSN: | 0194-911X |
| ISSN (Online): | 1524-4563 |
| Published Online: | 12 September 2016 |
| Copyright Holders: | Copyright © 2016 American Heart Association Inc. |
| First Published: | First published in Hypertension 68(5):1179-1190 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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