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Published on: March 18, 2021
Suppression of angiotensin II-induced pathological changes in heart and kidney by the caveolin-1 scaffolding domain
Panneerselvam Chinnakkannu1, Charles Reese2, John Antony Gaspar3
1Division of Cardiology, Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Abstract:
Dysregulation of the renin-angiotensin system leads to systemic hypertension and maladaptive fibrosis in various organs. We showed recently that myocardial fibrosis and the loss of cardiac function in mice with transverse aortic constriction (TAC) could be averted by treatment with the caveolin-1 scaffolding domain (CSD) peptide. Here, we used angiotensin II (AngII) infusion (2.1 mg/kg/day for 2 wk) in mice as a second model to confirm and extend our observations on the beneficial effects of CSD on heart and kidney disease. AngII caused cardiac hypertrophy (increased heart weight to body weight ratio (HW/BW) and cardiomyocyte cross-sectional area); fibrosis in heart and kidney (increased levels of collagen I and heat shock protein-47 (HSP47)); and vascular leakage (increased levels of IgG in heart and kidney). Echocardiograms of AngII-infused mice showed increased left ventricular posterior wall thickness (pWTh) and isovolumic relaxation time (IVRT), and decreased ejection fraction (EF), stroke volume (SV), and cardiac output (CO). CSD treatment (i.p. injections, 50 μg/mouse/day) of AngII-infused mice significantly suppressed all of these pathological changes in fibrosis, hypertrophy, vascular leakage, and ventricular function. AngII infusion increased β1 and β3 integrin levels and activated Pyk2 in both heart and kidney. These changes were also suppressed by CSD. Finally, bone marrow cell (BMC) isolated from AngII-infused mice showed hyper-migration toward SDF1. When AngII-infused mice were treated with CSD, BMC migration was reduced to the basal level observed in cells from control mice. Importantly, CSD did not affect the AngII-induced increase in blood pressure (BP), indicating that the beneficial effects of CSD were not mediated via normalization of BP. These results strongly indicate that CSD suppresses AngII-induced pathological changes in mice, suggesting that CSD can be developed as a treatment for patients with hypertension and pressure overload-induced heart failure.
Insights
The caveolin-1 scaffolding domain (CSD) peptide prevents heart and kidney damage caused by angiotensin II (AngII) in mice. CSD treatment improved cardiac function and reduced fibrosis and vascular leakage without lowering blood pressure.
Area of Science:
- Cardiovascular Research
- Renal Physiology
- Molecular Medicine
Background:
- Renin-angiotensin system (RAS) dysregulation causes hypertension and organ fibrosis.
- Previous studies demonstrated the protective effects of caveolin-1 scaffolding domain (CSD) peptide against cardiac dysfunction in a transverse aortic constriction (TAC) model.
- Angiotensin II (AngII) infusion serves as a critical model for studying hypertension-induced organ damage.
Purpose of the Study:
- To investigate the efficacy of CSD peptide in ameliorating AngII-induced cardiac and renal pathologies.
- To elucidate the molecular mechanisms underlying CSD's protective effects against AngII-induced damage.
- To assess CSD's impact on cardiac function, fibrosis, vascular leakage, and cellular signaling pathways.
Main Methods:
- Angiotensin II (AngII) infusion in mice to induce hypertension and organ damage.
- Treatment with caveolin-1 scaffolding domain (CSD) peptide via intraperitoneal injections.
- Assessment of cardiac hypertrophy, fibrosis (collagen I, HSP47), vascular leakage (IgG), and cardiac function (echocardiography).
- Analysis of integrin expression (β1, β3), Pyk2 activation, and bone marrow cell (BMC) migration towards SDF1.
Main Results:
- AngII infusion led to cardiac hypertrophy, fibrosis, vascular leakage, and impaired cardiac function.
- CSD treatment significantly reversed these pathological changes in the heart and kidneys.
- CSD suppressed AngII-induced increases in β1 and β3 integrins, Pyk2 activation, and hyper-migratory BMCs.
- CSD's beneficial effects were observed without altering AngII-induced hypertension.
Conclusions:
- CSD peptide effectively suppresses AngII-induced cardiac and renal pathological alterations.
- CSD's protective mechanisms involve modulating integrin signaling, Pyk2 activation, and bone marrow cell migration.
- CSD represents a potential therapeutic agent for treating hypertension and heart failure associated with pressure overload.
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