Exogenous Transforming Growth Factor-β1 and Its Mimic Heligmosomoides polygyrus TGM Attenuate the Heart's Inflammatory Response to Ischemic Injury and Reduce Mature Scar Size.

Successful and timely coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released endogenously in response to infection or tissue injury, and the goal of this study was to investigate its protective effects when given exogenously after MI. In patients with STEMI, we observed a significant correlation (P = 0.003) between higher circulating TGF-β1 levels at 24 hours after MI and a reduction in infarct size during the following 3 months, suggesting that an early increase in circulating TGF-β1 is protective. Using a mouse model of cardiac ischemia reperfusion, we demonstrate that exogenous TGF-β1 delivered in the acute care setting has multiple benefits. At 24 hours after reperfusion, exogenous TGF-β1 leads to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of the inflammatory cytokines IL-1β and chemokine (C-C motif) ligand 2 (>50% reduction, P = 0.038 and 0.0004, respectively), and reduced scar size at 4 weeks (21% reduction, P = 0.015). Furthermore, delivery of an equivalent dose of Heligmosomoides polygyrus TGM, a low-fibrogenic mimic of TGF-β1 secreted by a helminth parasite to evade immune rejection, has an almost identical protective effect on injured mouse hearts. Finally, using a genetic approach, we found that this benefit is mediated by TGF-β signaling in the vascular endothelium.