Related Experiment Video
Updated: Mar 15, 2026
A Model of Cardiac Remodeling Through Constriction of the Abdominal Aorta in Rats
Published on: December 2, 2016
c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced
Glaucia E Callera1, Tayze T Antunes1, Ying He1
1From 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.).
Insights
Downregulating c-Src kinase in mice attenuated angiotensin II-induced hypertension and improved cardiovascular function. However, c-Src inhibition did not benefit cardiac fibrosis, suggesting a complex role in hypertension.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Hypertension Pathophysiology
Background:
- Angiotensin II (Ang II) signaling is crucial in hypertension.
- The role of c-Src (a Src family kinase) in Ang II-induced hypertension and cardiovascular damage in vivo was previously unknown.
- Understanding c-Src's role is vital for developing targeted hypertension therapies.
Purpose of the Study:
- To investigate the in vivo role of c-Src in the development of Ang II-induced hypertension.
- To assess the impact of c-Src modulation on endothelial dysfunction, cardiac function, oxidative stress, and vascular remodeling.
- To elucidate the signaling pathways influenced by c-Src in the context of hypertension.
Main Methods:
- Utilized Angiotensin II-infused mice with partial c-Src deletion (c-Src+/-) and wild-type (WT) mice.
- Administered a specific c-Src inhibitor (CGP077675) to WT mice.
- Measured blood pressure, endothelial function, vascular wall thickness, cardiac function (ejection fraction, fractional shortening), oxidative stress markers, and signaling pathway activation (ERK1/2, JNK).
Main Results:
- c-Src partial deletion or inhibition ameliorated Ang II-induced hypertension, endothelial dysfunction, and cardiac dysfunction.
- Reduced oxidative stress and normalized vascular signaling (ERK1/2, JNK) were observed in c-Src-modulated mice.
- While c-Src downregulation improved function, it did not prevent Ang II-induced increases in vascular fibronectin, cardiac fibrosis, or inflammation.
Conclusions:
- c-Src plays a significant role in mediating Ang II-dependent hypertension and associated cardiovascular functional impairments.
- Downregulation of c-Src improves endothelial and cardiac function and reduces oxidative stress in this model.
- c-Src's role appears divergent, being more critical for regulating redox-sensitive cardiac and vascular function than for fibrosis and remodeling.
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.
Related Concept Videos
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:30Antihypertensive Drugs: Angiotensin II Receptor Blockers
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:17Antihypertensive Drugs: Action of β1 Blockers
01:30Heart Failure V: Medical Management