c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced Hypertension.
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.
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.).
Glaucia E
GE
Callera
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.).
Tayze T
TT
Antunes
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.).
Ying
Y
He
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.).
Augusto C
AC
Montezano
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.).
Alvaro
A
Yogi
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.).
Carmine
C
Savoia
From the Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada (G.E.C., T.T.A., Y.H., A.C.M., A.Y., R.M.T.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.C.M., R.M.T.); and Clinical and Molecular Medicine Department, Cardiology Unit, Sapienza University of Rome, Rome, Italy (C.S.). rhian.touyz@glasgow.ac.uk.
Rhian M
RM
Touyz
D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010766:Phosphorylation; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012680:Sensitivity and Specificity; D020257:Ventricular Remodeling / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D017382:Reactive Oxygen Species; D000804:Angiotensin II; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
angiotensin II; arteries; hypertension; oxidative stress; phosphorylation