Upregulation of protein and gene expression of arginase-1 in patients with ST elevation myocardial infarction

Abstract Background The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unknown. Increased arginase-1 activity leads to reduced nitric oxide production and increased formation of reactive oxygen species due to uncoupling of the endothelial nitric oxide synthase (eNOS). These events lead to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. Experimental studies have shown that arginase-1 expression and activity are increased in atherosclerosis and during myocardial ischemia-reperfusion. Accordingly, inhibition of arginase-1 reduces atherosclerotic lesion development and limits the extent of infarct size during ischemia-reperfusion via an eNOS-dependent mechanism. Furthermore, arginase-1 inhibition improves endothelial function in patients with coronary artery disease but the potential role of arginase-1 in patients with STEMI is poorly understood. Purpose The purpose of the current study was to test the hypothesis that arginase-1 is upregulated and correlate to infarct size in STEMI patients. Methods and results Two independent cohorts of STEMI patients were included. In cohort 1, plasma and buffy coat leukocytes were collected from 53 STEMI patients at the time of arterial puncture for percutaneous coronary intervention, at 24–48 hours post STEMI and at 3 months post STEMI. Gene expression in leukocytes was determined in 51 patients with Affymetrix Human Transcriptome Array 2.0. In cohort 2, plasma was collected from 82 STEMI patients at admission and at 6 months for determination of plasma arginase-1. These patients underwent cardiac magnetic resonance imaging performed at day 4–7 and at 6 months post STEMI. Plasma arginase-1 levels were quantified with ELISA. Control blood samples were collected from 56 healthy age matched subjects. In cohort 1, ARG1 gene expression was four-fold higher in STEMI patients at admission compared to controls (Figure A). This expression returned to control levels within 3 months. Plasma arginase-1 levels were two times higher in STEMI patients at admission compared to controls, and remained elevated at 24–48 hours and at 3 months post STEMI (Figure B). The increase in plasma arginase-1 in STEMI patients was confirmed in cohort 2 (Figure C). Arginase-1 levels did not correlate with infarct size. Conclusions STEMI patients demonstrate increased gene expression and plasma levels of arginase-1 in the acute setting. In contrast to gene expression plasma arginase-1 levels remain significantly elevated over time. The markedly increased expression of arginase-1 already at admission may suggest a mechanistic role of arginase-1 in the development of STEMI. Further studies are needed to elucidate whether increased expression, induction and activity of arginase-1 are contributing factors for the development of STEMI.