I?B? attenuates angiotensin II-induced cardiovascular inflammation and fibrosis in mice.
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ABSTRACT: The development of cardiovascular fibrosis is associated with chronic inflammation, where activation of nuclear factor ?B (NF-?B) signaling may play a critical role. NF-?B activation is tightly regulated by the cellular inhibitor of ?B (I?B) family of proteins, such as I?B? and I?B?. I?B? and I?B? display different regulation kinetics in response to inflammatory stimulation. The present study tested the hypothesis that I?B? and I?B? may have different roles in modulating cardiovascular inflammation and fibrosis, using a model of angiotensin II infusion-induced hypertension in wild-type mice and I?B? knock-in mice, in which the I?B? gene is replaced by I?B? cDNA (AKBI). In WT mice, subcutaneous angiotensin II infusion for 7 days induced increased perivascular and interstitial collagen deposition and fibrotic lesions, associated with myocardial interstitial hemosiderin accumulation and extensive macrophage infiltration. These effects of angiotensin II were dramatically limited in AKBI mice. Replacement of I?B? with I?B? significantly attenuated angiotensin II infusion-induced expression of interleukin 1?, interleukin 6, monocyte chemotactic protein 1, collagen I and III, fibronectin, and tissue inhibitor of metalloproteinase 1 in the hearts. Furthermore, using cultured vascular smooth muscle cells, we demonstrated that interleukin 1?-induced NF-?B activation and monocyte chemotactic protein 1, vascular cell adhesion molecule 1, and tissue inhibitor of metalloproteinase 1 expressions were suppressed in the AKBI cells because of the replacement of I?B? with I?B?. These results indicate that NF-?B has an essential role in mediating the cardiovascular inflammatory response to angiotensin II and suggest that targeting the balance of I?B? and I?B? expression might be a novel therapeutic modality in preventing fibrosis in hypertensive cardiovascular disease.
SUBMITTER: Xu S
PROVIDER: S-EPMC3141280 | biostudies-literature | 2011 Aug
REPOSITORIES: biostudies-literature
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