Fibroblast-specific IKK-beta deficiency ameliorates angiotensin II-induced adverse cardiac remodeling in mice

Cardiac inflammation and fibrosis contribute significantly to hypertension-related adverse cardiac remodeling. IKB kinase beta (IKK-beta), a central coordinator of inflammation through activation of NF-KB, has been demonstrated as a key molecular link between inflammation and cardiovascular disease. However, the cell-specific contribution of IKK-beta 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-beta, we generated inducible fibroblast-specific IKK-beta-deficient mice. Here, we report an important role of IKK-beta in the regulation of fibroblast functions and cardiac remodeling. Fibroblast-specific IKK-beta- deficient male mice were protected from angiotensin II-induced cardiac hypertrophy, fibrosis, and macrophage infiltration. Ablation of fibroblast IKK-beta inhibited angiotensin II-stimulated fibroblast proinflammatory and profibrogenic responses, leading to ameliorated cardiac remodeling and improved cardiac function in IKK-beta-deficient mice. Findings from this study establish fibroblast IKK-beta as a key factor regulating cardiac fibrosis and function in hypertension-related cardiac remodeling.