Abstract
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.
Highlights
Cardiac remodeling is a major process responsible for end-stage heart failure, a leading cause of morbidity and mortality worldwide [1,2,3]
The mRNA and protein levels of IKK-β were significantly decreased in cardiac fibroblasts infected with lentivirus expressing Cre as compared with those transduced with control lentivirus (Figure 1, A and B)
Quantitative PCR and immunoblotting analyses confirmed that angiotensin II (Ang II) treatment stimulated the expression of fibrotic markers, including αSMA, collagen 1a1 (Col1a1), and collagen 3a1 (Col3a1), in control but not IKK-β–knockdown fibroblasts (Figure 1, E and G)
Summary
Cardiac remodeling is a major process responsible for end-stage heart failure, a leading cause of morbidity and mortality worldwide [1,2,3]. Angiotensin II (Ang II), a key component of the renin-angiotensin system, plays an important role in the pathogenesis of cardiac remodeling by inducing hypertension and inflammation in a variety of cardiac diseases [5]. Many inflammatory signaling pathways that contribute to cardiovascular disease are regulated by the transcriptional factor NF-κB, a master regulator of the innate and adaptive immune responses [9,10,11]. We found that deficiency of myeloid IKK-β reduced macrophage inflammatory responses and decreased diet-induced atherosclerosis in hyperlipidemic, LDL receptor-deficient (LDLR–/–) mice [13]. Deletion of IKK-β in smooth muscle cells protected LDLR–/– mice from diet-induced vascular inflammation and atherosclerosis [11]. Targeted deletion of IKK-β in mature adipocytes affects adipose remodeling, tissue inflammation, and atherosclerotic plaque vulnerability in obese LDLR–/– mice [20]
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