Abstract 263: Inhibition of Angiotensin II Signaling on LysM+ Myelomonocytic Cells and Their Depletion Improves Vascular Endothelial Dysfunction in Mice With Heart Failure After Myocardial Infarction

Abstract

Background: Myocardial infarction (MI) induced heart failure (HF) leads to impaired left ventricular function and endothelial dysfunction accompanied by a systemic inflammatory reaction. So far the effects of inhibition of angiotensin II-signaling in heart failure after MI regarding the endothelial function are not fully understood. Methods and Results: 8-12 weeks old male C57BL/6 mice were subjected to permanent ligation of the left anterior descending artery (LAD) to induce ischemic heart failure. We measured a reduced vascular endothelial and smooth muscle function in isolated aortic segments 7d and 28d post MI in isometric tension studies. Vascular superoxide formation and vascular mRNA expression of monocyte chemoattractant protein-1 ( ccl2 ), vascular cellular adhesion molecule-1 ( vcam-1 ), inducible NO synthase ( nos2 ), and angiotensin II receptor type 1 ( agtr1 ) were increased in HF mice compared to sham. Flow cytometry analysis of aortic tissue of HF mice revealed an increased accumulation of CD45+ immune cells in the aortic wall, including CD11b+Gr-1lowF4/80+ macrophages and Ly6C+ monocytes. Diphteria toxin mediated depletion of lysozyme M positive cells starting 28d after MI using LysM-Cre-iDTR mice improved the endothelial function in HF mice. To test specific effects of ATII-signaling on endothelial function in heart failure we administered ramipril (10mg/kg bodyweight) or telmisartan (40mg/kg bodyweight), respectively, via drinking water, starting 1d after MI. After 28d, we assessed an improved vascular endothelial and smooth muscle function, less vascular superoxide production, less accumulation of CD45+ immune cells, reduced aortic expression of ccl2, vcam-1, nos2 and agtr1 mRNA of HF mice treated with ramipril as well as with telmisartan in comparison to non-treated HF controls. Importantly, left ventricular dimensions and ejection fraction was not different in treated and non-treated mice, implying a direct anti-inflammatory effect on the vasculature. Conclusion: Our results suggest that vascular dysfunction post MI is at least in part mediated by angiotensin II, driving vascular accumulation of inflammatory monocytes and direct effects on vascular oxidative stress levels.