Abstract MP221: Early Recruitment Of Neutrophils To The Ischemic Heart Is Orchestrated By Catecholamine-induced Demargination

Abstract

Myocardial infarction (MI) induces a rapid and robust inflammatory response characterized by infiltration of different leukocyte cell types to the infarcted heart. Neutrophils are the first cells to arrive at the infarct where they release a plethora of proteolytic enzymes, exacerbate tissue injury, expand infarct size and promote cardiac dysfunction/ failure. We previously have shown that granulopoiesis (in the bone marrow, BM) is the major source of neutrophils during MI. However, the increase in the number of neutrophils at the infarct begins much earlier than the peak response in the BM (~ 24 hours) suggesting that sources other than granulopoiesis may contribute to the overall neutrophil pool. Because the marginated pool of neutrophils represents the same size of circulating pool, we hypothesized that demargination of neutrophils from the vascular wall contribute to the neutrophil burden in the heart, particularly during the early hours after MI.Using a mouse model of the permanent ligation of the left anterior descending coronary artery, BM ablation of hematopoietic stem cells, flow cytometry and BM transplant techniques, we found that the first wave of neutrophils recruited to the ischemic heart are exclusively sourced from the vasculature and not granulopoiesis in the BM/ spleen. The neutrophils recruited at the heart bore all hallmarks of demargination induced by dexamethasone including decreased F-actin, CD62L, and increased Adam17 expression. The recruitment of neutrophils is orchestrated by catecholamine stress as experimental strategies aimed at blockade of β1 and β2 adrenergic receptors (AR) reduced neutrophil burden in the ischemic heart. Interestingly, despite a decrease in neutrophil burden, the cardiac function did not improve but rather declined. However, short-term inhibition (6-12 hours post-MI) of β AR system either by receptor blockade (propranolol) or inhibition of catecholamine synthesis (AMPT) not only reduced neutrophil burden but also significantly improved cardiac function. Together these data suggest that catecholamine stress induced-demargination constitute the major source of neutrophils during the early hours post-MI. Pharmacological strategies aimed at suppressing the initial onslaught of neutrophils on the ischemic heart may represent a novel and viable approach towards a better resolution of the injury. Currently, studies are underway to define the signaling mechanisms that drive demargination and, to optimize the dose/ duration of a specific β receptor blocker to achieve better functional outcomes.