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

• Published in: JCI insight 2021-09, Vol.6 (18)
• Main Authors: Lu, Weiwei, Meng, Zhaojie, Hernandez, Rebecca, Zhou, Changcheng
• Format: Article
• Language: English
• Subjects: Angiotensin II - pharmacology; Animals; Blood Pressure - drug effects; Cardiology; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cell Differentiation - drug effects; Cell Movement; Cell Proliferation; Cells, Cultured; Collagen Type I - metabolism; Fibroblasts - physiology; Fibrosis; Gene Knockdown Techniques; Heart Rate - drug effects; Hypertension - chemically induced; I-kappa B Kinase - genetics; Inflammation - metabolism; Macrophages; Male; Mice; Myocarditis - genetics; Myocarditis - metabolism; Myocardium - pathology; Organ Size; Protective Factors; Signal Transduction; Ventricular Remodeling - genetics
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.150161

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.