Abstract 18995: Absence of the NLRP3 Inflammasome Improves Survival but Not Cardiac Remodeling Following Myocardial Infarction
Introduction: Myocardial infarction (MI) causes a sterile inflammatory response through activation of the innate immune system. Upon activation of NLRP3, a cytosolic pattern recognition receptor, inflammasomes are formed together with scaffold protein ASC and caspase-1. This leads to maturation of the IL-1 family cytokines. While the inflammatory response is a prerequisite for healing of the infarction, a dysregulated response may have unbeneficial effects promoting cardiac remodeling. In this study we investigated whether absence of NLRP3 affects post-MI remodeling.
Methods and Results: C57Bl/6J (WT) and NLRP3 knock-out (NLRP3 KO) mice were subjected to an MI by coronary artery ligation. WT mice had a high mortality rate (43%) primarily due to ventricular rupture at day 4-6. The mortality rate was markedly reduced in NLRP3 KO mice (17%, p<0.05), despite comparable infarct sizes and heart function 1 day post-MI. Careful evaluation of cardiac dimensions by MRI and macrophage accumulation by histology did not reveal any differences in cardiac remodeling up to 21 days post-MI. However, NLRP3 KO mice showed a decreased expression of ANP, IL-6 and matrix metalloproteinases in the infarcted area. These observations point at a primary role of NLRP3 in infarction healing. To investigate this more closely, male WT and NLRP3 KO bone marrow chimeras were created and an MI was induced. Transplantation of NLRP3 KO bone marrow into WT mice greatly improved post-MI survival compared to WT to WT controls (100% vs. 53% survival, p<0.001). In addition, cardiac function measured by echocardiography was improved accordingly in NLRP3 KO chimeras (p=0.06).
Conclusions: NLRP3 activation in hematopoietic cells infiltrating in the myocardium disturbs infarction healing, thereby causing ventricular rupture. Ongoing studies aim at defining which specific cell type is mediating this effect.
Author Disclosures: M.C. Louwe: None. O.J. Kaasbøll: None. K. Alfsnes: None. A. Rashidi: None. E. Schrumpf: None. S.B. Haugstad: None. E. Melum: None. H. Attramadal: None. I. Sjaastad: None. P. Aukrust: None. A. Yndestad: None.
- © 2016 by American Heart Association, Inc.