IκBβ Attenuates Angiotensin II–Induced Cardiovascular Inflammation and Fibrosis in Mice
The development of cardiovascular fibrosis is associated with chronic inflammation, where activation of nuclear factor κB (NF-κB) signaling may play a critical role. NF-κB activation is tightly regulated by the cellular inhibitor of κB (IκB) family of proteins, such as IκBα and IκBβ. IκBα and IκBβ display different regulation kinetics in response to inflammatory stimulation. The present study tested the hypothesis that IκBα and IκBβ may have different roles in modulating cardiovascular inflammation and fibrosis, using a model of angiotensin II infusion-induced hypertension in wild-type mice and IκBβ knock-in mice, in which the IκBα gene is replaced by IκBβ 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 IκBα with IκBβ significantly attenuated angiotensin II infusion–induced expression of interleukin 1β, 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 1β–induced NF-κB 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 IκBα with IκBβ. These results indicate that NF-κB has an essential role in mediating the cardiovascular inflammatory response to angiotensin II and suggest that targeting the balance of IκBα and IκBβ expression might be a novel therapeutic modality in preventing fibrosis in hypertensive cardiovascular disease.
- Received February 20, 2011.
- Revision received March 4, 2011.
- Accepted May 16, 2011.
- © 2011 American Heart Association, Inc.