Cardiac inflammation and fibrosis contribute significantly to hypertension-related adverse cardiac remodeling. IκB kinase β (IKK-β), a central coordinator of inflammation through activation of NF-κB, has been demonstrated as a key molecular link between inflammation and cardiovascular disease. However, the cell-specific contribution of IKK-β signaling toward adverse cardiac remodeling remains elusive. Cardiac fibroblasts are one of the most populous nonmyocyte cell types in the heart that play a key role in mediating cardiac fibrosis and remodeling. To investigate the function of fibroblast IKK-β, we generated inducible fibroblast-specific IKK-β–deficient mice. Here, we report an important role of IKK-β in the regulation of fibroblast functions and cardiac remodeling. Fibroblast-specific IKK-β–deficient male mice were protected from angiotensin II–induced cardiac hypertrophy, fibrosis, and macrophage infiltration. Ablation of fibroblast IKK-β inhibited angiotensin II–stimulated fibroblast proinflammatory and profibrogenic responses, leading to ameliorated cardiac remodeling and improved cardiac function in IKK-β–deficient mice. Findings from this study establish fibroblast IKK-β as a key factor regulating cardiac fibrosis and function in hypertension-related cardiac remodeling.
Weiwei Lu, Zhaojie Meng, Rebecca Hernandez, Changcheng Zhou