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.
Highlights
Metabolic syndromes such as hypertension, obesity, and/or diabetes mellitus often cause organ fibrosis, primarily affecting the heart and kidney and contribute to the development of congestive heart failure (CHF)
We first determined heart weight to body weight ratio (HW/BW ratio) for: Sham mice treated with vehicle (Sham+Veh), Sham mice treated with caveolin-1 scaffolding domain (CSD) (Sham+CSD), AngII mice treated with vehicle (AngII+Veh), and AngII mice treated with CSD (AngII+CSD)
The beneficial effects of CSD were found to be accompanied by reduced expression of collagen I, heat shock protein-47 (HSP47), and integrins (β1 and β3), and by the reduced activation of nonreceptor tyrosine kinases (NTKs) (Pyk2 and c-Src)
Summary
Metabolic syndromes such as hypertension, obesity, and/or diabetes mellitus often cause organ fibrosis, primarily affecting the heart and kidney and contribute to the development of congestive heart failure (CHF). The activation of angiotensin receptor 1 (AT1) by AngII mediates the development of cardiac and renal fibrosis [2,3,4] by stimulating synthesis of proinflammatory cytokines, chemokines, adhesion molecules, and growth factors that in turn activate their cognate receptors to promote the proliferation and differentiation of fibroblasts into myofibroblasts that express extracellular matrix (ECM) proteins at high levels [5] These processes involve AngII upregulation of TGFβ expression in both cardiomyocytes and cardiac fibroblasts and the resulting contributions of AngII and TGFβ signaling to fibrosis and cardiac hypertrophy as part of pathological ventricular remodeling [4]. Other independent studies show proliferating fibroblast-like cells near blood vessels, suggesting the possible role of endothelial cells and pericytes as precursors of myofibroblasts [27, 28]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
