Abstract 212: Role of Monocytes and Inflammation in Vascular Endothelial Dysfunction in Mice With Heart Failure After Myocardial Infarction
Background: Heart failure (HF) after myocardial infarction (MI) leads to impaired left ventricular function and reduced blood flow in peripheral arteries. Angiotensin II (ATII) signaling is crucial in MI, and inflammatory myelomonocytic cells are involved in the process of ATII-induced vascular dysfunction. Their role in MI-mediated vascular dysfunction has not been defined yet.
Objective: Test the impact of selective depletion of lysozyme M positive (LysM+) myelomonocytic cells on endothelial dysfunction in a model of ischemic heart failure in mice
Methods and results: 8 to 12 week old mice (C57B6 background) were subjected to permanent coronary ligation of the left anterior descending artery (LAD) to induced HF post MI. We measured a reduced vascular endothelial and smooth muscle function in isolated aortic segments 7d and 28d post MI in isometric tension studies. Also the production of vascular superoxide (chemiluminescence, oxidative fluorescence microtopography) and vascular mRNA expression of MCP-1, VCAM-1, IL-6 and ATII receptor type 1 were increased (assessed by mRNA reverse transcription polymerase chain reaction) in HF mice compared to sham. FACS analysis of aortic tissue of HF mice shows an increased infiltration of CD45+ immune cells in the aortic wall, including CD11b+Gr-1lowF4/80+ monocytes/macrophages. Using mice with LysM dependent cre-inducible expression of diphtheria toxin receptor (LysMCreIDTR) we selectively ablated LysM+ myelomonocytic cells 28d after MI for 10d via diphtheria toxin. We assessed a significantly improved vascular endothelial and smooth muscle function, less vascular superoxide production and a reduced expression of VCAM-1 and ATII receptor type 1 in aortic tissue. The number of circulating monocytes in blood was reduced, while the cardiac function (EF (%), LV size) in sonography stays constant between depleted and non-depleted HF mice.
Conclusion: Our results suggest that vascular dysfunction post MI is at least in part mediated by inflammatory leukocyte infiltrating the vessel wall and that depletion of inflammatory monocytes in HF after MI improves the vascular function. It can potentially be a new target to protect endothelial function in HF and prevent secondary events after a MI.
Author Disclosures: M. Molitor: None. S. Finger: None. S. Kossmann: None. V.S. Garlapati: None. J. Lagrange: None. R. Schüler: None. T. Münzel: None. S. Karbach: None. M. Knorr: None. P. Wenzel: None.
- © 2015 by American Heart Association, Inc.