Myocardial infarction (MI) is the leading cause of mortality in the USA. Patients develop insulin resistance after acute MI. In a mouse model of MI, we found coronary ligation significantly increased insulin resistance in mice fed with either a chow diet or high fat diet. Recent studies have shown that MI-induced insulin resistance has direct proatherogenic effects at the level of atherosclerotic plaques leading to a series of cellular atherogenic events and plaque progression. But the mechanistic underpinnings of insulin resistance after MI are not explored. We have recently shown that MI increases production of inflammatory monocytes, which can infiltrate visceral adipose tissue (VAT) and differentiate into macrophages. Consistently, our preliminary data revealed that MI-induced insulin resistance was associated with accumulation of CX3CR1+ CCR2+ monocyte-derived macrophages in VAT. We hypothesize that the influx of monocyte-derived macrophages into VAT after MI creates an inflammatory milieu, resulting in insulin resistance. We will test the hypothesis in three specific aims. 1.We will investigate the dynamics of macrophage subsets in VAT after MI. We will use flow cytometry and intravital microscopy to investigate monocyte accumulation in VAT after MI. 2.To test the mechanisms of MI-induced insulin resistance, we will investigate if loss of M-CSF after MI leads to insulin resistance. Our preliminary experiments showed that coronary ligation in mice reduced systemic levels of M-CSF, a cytokine responsible for tissue resident macrophage survival. 3. We will investigate if the accumulation of monocyte-derived macrophages induces insulin resistance after MI using a mouse strain of tamoxifen-inducible CX3CR1. Furthermore, since monocyte-derived VAT macrophages express high levels of IL-1?, we will use IL-1? neutralizing antibody to explore whether it can improve insulin sensitivity. The proposed grant application will further our understanding of mechanisms behind MI-induced insulin resistance and explore new therapeutic avenues.

Public Health Relevance

Patients with acute myocardial infarction develop insulin resistance. However, the cause of the increased insulin resistance after myocardial infarction is not known. Understanding changes in the composition of macrophage subsets in visceral adipose tissue will significantly improve our knowledge on drug development to treat insulin resistance after myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL143967-02
Application #
9665768
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Chen, Jue
Project Start
2018-04-01
Project End
2023-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Florentin, Jonathan; Coppin, Emilie; Vasamsetti, Sathish Babu et al. (2018) Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes. J Immunol 200:3612-3625