Abstract 549: Interleukin-6 Trans-Signaling in Acute Myocardial Infarction in Male BALB/c Mice

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine historically associated with development and/or maintenance of cardiovascular disease (CVD). Despite this long-standing association, the discrete roles of IL-6 on the pathogenesis or severity of CVD and notably acute myocardial infarction (AMI) remain unclear. Dogma contends that IL-6 mediates effects largely through direct interaction with a membrane-bound IL-6 receptor (IL-6R) on leukocytes and hepatocytes. Intriguingly, identification of a soluble receptor for IL-6 (sIL-6R) has invigorated study into a regulatory role of IL-6 trans-signaling (IL-6trans) in CVD pathogenesis. IL-6trans provokes signal transduction in cells lacking the membrane-bound receptor, including notably cardiomyocytes, and ultimately activates STAT3 gene transcription and stabilizes mitochondrial function, thereby promoting cardioprotection. In this study we hypothesized that IL-6trans plays a crucial role in the injury response to AMI by increasing circulating IL-6 and sIL-6R and inducing cardioprotection via STAT3. To test this hypothesis, male BALB/c mice were subjected to acute ischemia (30 min) of the LAD coronary artery (to mimic AMI) with/without reperfusion and with/without inclusion of a pre- or post-ischemic conditioning event in order to determine regulatory involvement of IL-6trans in acute cardioprotection. Following surgery, ischemic regions of left ventricle (LV) and sera were analyzed for IL-6, sIL-6R, and activated (phosphorylated) STAT3. Results show that AMI led to increases in serum IL-6 (p=0.0053) and sIL-6R (p=0.0023) as well as in LV phosphorylated (Tyr705) STAT3 (p=0.0059) compared to naïve LV tissues. Preliminary data from ischemic pre- and post-conditioning regimens were independently associated with increases in IL-6trans demonstrated by trending increases in LV STAT3 phosphorylation (Ser727, Tyr705) compared to naïve controls. These inclusive data on IL-6trans suggest it serves a biologically significant intrinsic role in mediating acute protection following AMI. We anticipate that continued investigation will firmly establish IL-6trans as a unique protective pathway that could be targeted in order to improve morbidity and mortality of AMI patients.