c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced Hypertension

Hypertension. 2016 Nov;68(5):1179-1190. doi: 10.1161/HYPERTENSIONAHA.116.07699. Epub 2016 Sep 12.

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.

Keywords: angiotensin II; arteries; hypertension; oxidative stress; phosphorylation.

MeSH terms

  • Analysis of Variance
  • Angiotensin II / pharmacology
  • Animals
  • Blotting, Western
  • CSK Tyrosine-Protein Kinase
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / prevention & control
  • Cells, Cultured
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fibrosis / metabolism
  • Fibrosis / physiopathology
  • Hypertension / chemically induced
  • Hypertension / physiopathology*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / cytology
  • Phosphorylation
  • Random Allocation
  • Reactive Oxygen Species / metabolism*
  • Sensitivity and Specificity
  • Ventricular Remodeling / physiology*
  • src-Family Kinases / metabolism*

Substances

  • Reactive Oxygen Species
  • Angiotensin II
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • Extracellular Signal-Regulated MAP Kinases