Abstract 18422: NLRP3 Inflammasome Promote Myocardial Remodeling During Diet-Induced Obesity
Introduction: Type 2 diabetes (T2D) is a risk factor for heart failure. We have demonstrated that NLRP3 inflammasome is functional in the heart and may regulate cardiac dysfunction and cell death.
Hypothesis: This led us to hypothesize that the NLRP3 inflammasome may play a role in development of cardiomyopathy in T2D. The present project aims to explore this hypothesis by examining NLRP3 and ASC deficient mice in a model of metabolic stress-induced cardiomyopathy.
Methods: Wt (C57Bl/6J), NLRP3-/- and ASC-/- male mice were fed a high-fat diet (HFD; 60%cal from fat) or control diet for 52 weeks. Echocardiography and measurements of fasting plasma glucose were performed during the study period. Systolic and diastolic blood pressures were measured using the tail-cuff method.
Results: HFD induced increase in body weight in all mice, but Wt mice gained significantly more. Wt mice on HFD also had significantly higher fasting plasma glucose levels. Long-term exposure to HFD induced elevation in left ventricle (LV) mass in all mice. Wt-HFD mice had a three-fold increase in liver weight indicating liver steatosis; this was reduced in NLRP3-/- mice but not significant in ASC-/- mice. Cardiac structure and function were evaluated using echocardiography. Wt-HFD mice had significantly increased LV wall thickness, diameter and relative wall thickness (RWT), indicating concentric hypertrophy. These structural changes were much less pronounced in NLRP3-/- and ASC-/- mice on HFD, with no significant changes in wall thicknesses and RWT. Both systolic and diastolic blood pressure were increased in mice fed a HFD, and Wt-HFD mice showed a significantly greater increase in comparison to the NLRP3-/- HFD mice, but not significant in ASC-/- mice on HFD. This may explain the cardiac hypertrophic response in Wt-HFD mice. LV fractional shortening (FS), was not reduced in Wt-HFD mice, but significantly reduced in NLRP3-/- and ASC-/- mice. However, FS values were maintained within the normal range, indicating preserved myocardial function.
Conclusions: Long-term HFD induces development of LV concentric hypertrophy. We did not observe these changes in NLRP3 or ASC deficient mice, suggesting that the NLRP3 inflammasome plays a role in development of diabetic cardiomyopathy.
Author Disclosures: T. Ranheim: None. M. Sokolova: None. I. Sjaastad: None. K. Alfsnes: None. M. Louwe: None. M. Aronsen: None. L. Shang: None. S.B. Haugstad: None. M. Bliksøen: None. E. Lien: None. P. Aukrust: None. A. Yndestad: None.
- © 2014 by American Heart Association, Inc.