Abstract 174: Role of Cardiomyocyte-Localized Nuclear Factor (NF)-κB in Diet-Induced Diabetic Cardiomyopathy
Role of Inflammatory signaling in the development of obesity- and type 2 diabetes (T2D)-associated cardiomyopathy remains unclear. We hypothesized that cardiomyocyte-specific inflammatory activation, independent of systemic inflammation, is sufficient for the genesis of diabetic cardiomyopathy. Wild-type (WT) and transgenic (Tg) C57BL/6 mice with myocyte-restricted overexpression of phosphorylation-resistant IκBα (IκBαS32A,S36A) were fed a high fat (HFD, 45% kcal fat) or control diet (CD, 10% kcal fat) for 28 weeks to induce obesity and T2D. These Tg mice exhibit attenuated NF-kB activation, a central regulator of inflammation. After 28 weeks of feeding, WT HFD mice exhibited increased body weight, hyperglycemia, hyperinsulinemia, insulin resistance, and glucose intolerance. In contrast, although HFD-fed Tg mice exhibited significantly (p < 0.05) increased body weight, the mice still maintained normal fasting blood glucose, insulin levels, and insulin sensitivity compared to CD Tg mice, indicating absence of overt T2D. Echocardiography revealed that both HFD-fed WT and Tg mice developed concentric left ventricular (LV) hypertrophy with increased septal and posterior wall thickness, decreased LV end-diastolic diameter and had unchanged LV ejection fraction suggesting development of LV hypertrophy in both strains regardless of the severity of the metabolic disorder. Analysis of mononuclear phagocyte cell profiles revealed similar trends in WT and IκB Tg mice. HFD fed mice had higher levels of pro-inflammatory (CD11b+Ly6chi) and anti-inflammatory (CD11b+Ly6clo) monocytes in the blood, heart, spleen and adipose tissue compared to CD fed mice. Analysis of antigen presenting cells indicated that HFD fed mice in both genotypes had significantly increased levels of both classical (CD11c+CD45R–) and plasmacytoid (CD11cintCD45R+) dendritic cells in blood, heart, spleen and adipose tissues compared to respective CD fed mice. Thus, we conclude that cardiomyocyte inflammation is central to the development of metabolic abnormalities related to obesity, whereas neither cardiomyocyte-specific nor systemic insulin resistance is required for the development of the hypertrophic cardiomyopathic phenotype.
Author Disclosures: M. Goel: None M.A. Ismahil: None T. Hamid: None S.D. Prabhu: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2014 by American Heart Association, Inc.