ACE Inhibition Modulates Myeloid Hematopoiesis after Acute Myocardial Infarction and Reduces Cardiac and Vascular Inflammation in Ischemic Heart Failure.

Wolf-Stephan Rudi,Stefanie Finger,Johannes Wild,Philip Wenzel,Susanne H Karbach,Thomas Münzel,Michael Molitor,Venkata Garlapati

doi:10.3390/antiox10030396

Abstract

Aims: Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a cornerstone of drug therapy after myocardial infarction (MI) and improve left ventricular function and survival. We aimed to elucidate the impact of early treatment with the ACE inhibitor ramipril on the hematopoietic response after MI, as well as on the chronic systemic and vascular inflammation. Methods and Results: In a mouse model of MI, induced by permanent ligation of the left anterior descending artery, immediate initiation of treatment with ramipril (10 mg/k/d via drinking water) reduced cardiac inflammation and the number of circulating inflammatory monocytes, whereas left ventricular function was not altered significantly, respectively. This effect was accompanied by enhanced retention of hematopoietic stem cells, Lin−Sca1−c-Kit+CD34+CD16/32+ granulocyte–macrophage progenitors (GMP) and Lin−Sca1−c-Kit+CD150−CD48− multipotent progenitors (MPP) in the bone marrow, with an upregulation of the niche factors Angiopoetin 1 and Kitl at 7 d post MI. Long-term ACE inhibition for 28 d limited vascular inflammation, particularly the infiltration of Ly6Chigh monocytes/macrophages, and reduced superoxide formation, resulting in improved endothelial function in mice with ischemic heart failure. Conclusion: ACE inhibition modulates the myeloid inflammatory response after MI due to the retention of myeloid precursor cells in their bone marrow reservoir. This results in a reduction in cardiac and vascular inflammation with improvement in survival after MI.

Highlights

Besides rapid revascularization, medical therapy substantially improves outcomes after acute myocardial infarction (MI)
It has been shown that AngII enhances vascular permeability, amplifies the expression of selectins on endothelial cells, platelets and leukocytes and regulates the expression of integrins such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) [6,7,8]
In order to investigate the beneficial effects of ramipril treatment in more detail, we performed flow cytometric analysis of infarcted myocardium 7 days after MI

Summary

Introduction

Medical therapy substantially improves outcomes after acute myocardial infarction (MI). Antiplatelet therapy, ß-blockers, statins and angiotensinconverting-enzyme inhibitors (ACE inhibitors) or angiotensin II receptor type 1 blockers (ARB) form the basis of drug treatment [1]. While the prevention and treatment of cardiovascular risk factors determine current therapeutic strategies, there is growing evidence that MI induces long-lasting changes in the immune system and hematopoiesis, which accelerates inflammation [2,3]. Several immune cells express angiotensin II receptors, primarily type 1, on their surface, which impacts downstream signaling and polarization [4]. Due to phosphorylation of NF-kB, AngII signaling directly influences the levels of inflammatory cytokines such as tumor. Antioxidants 2021, 10, 396 necrosis factor alpha (TNFα) or interleukin 1 beta (IL1ß), which are drivers of chronic inflammation in cardiovascular diseases [5]. It has been shown that AngII enhances vascular permeability, amplifies the expression of selectins on endothelial cells, platelets and leukocytes and regulates the expression of integrins such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) [6,7,8]

Results

Discussion

Conclusion