Abstract 5549: IκBα-Deficiency Attenuates Angiotensin II-Induced Cardiovascular Fibrosis in Mice
Abnormally increased angiotensin II (AngII) can induce cardiovascular hypertrophy and fibrosis, associated with increased inflammation. Activation of NFκB is essential to initiate inflammation, which is controlled by cellular inhibitor proteins IκB (including α, β, etc.). This study determined whether IκBα-deficiency (IκB−/−) could influence mouse cardiovascular remodeling in response to AngII. Wild-type (WT) and IκBα−/− mice (female, 5 months old) were infused for 6 days with either saline or AngII (3.2 mg/kg/day) via subcutaneous osmotic pumps (10 mice in each group). Cardiovascular inflammation and pathology were examined after the 6-day infusion. Masson’s trichrome stain shows that AngII infusion caused cardiomyocyte and coronary arterial smooth muscle hypertrophy, intimal injury, and adventitial fibroblast proliferation, as well as extensive ventricular interstitial fibrosis in hearts from WT mice, whereas these pathological changes, except for cardiomyocyte and arterial smooth muscle hypertrophy, were nearly absent in the hearts from AngII-infused IκBα−/− mice. Collagen deposition in ventricles significantly increased in AngII-infused WT mice (3.1±1.1 fold, p<0.05), but had no change in AngII-infused IκBα−/− mice (1.1±0.4 fold). Aortic media thickness was significantly increased to the same extent in both WT and IκBα−/− mice infused with AngII (saline vs. AngII: 51±2 μm vs. 78±6 μm in WT, p<0.001; 50±2 μm vs. 77±5 μm in IκB−/−, p<0.001). Adventitial cell proliferation and fibrosis were clearly seen in the aorta of AngII-infused WT mice, but absent in the aorta of AngII-infused IκBα−/− mice. Real-time RT-PCR revealed significantly different gene expression levels between the ventricular tissues from WT and IκBα−/− mice infused with AngII, including collagen I (12:2), collagen III (15:5), fibronetin (16:2), TIMP-1 (143:20), IL-1β (6:1), IL-6 (29:3), TNFα (3:1), and MCP-1 (5:3) (fold-increase in comparison to WT mice infused with saline, n=5, P<0.05). In conclusion, IκBα-mediated NFκB activation and inflammatory responses play critical roles in AngII inducing cardiovascular fibrosis but these inflammatory responses do not contribute to AngII-induced cardiovascular hypertrophy.
This research has received full or partial funding support from the American Heart Association, AHA National Center.