Cardiac repair after myocardial infarction is controlled by a complement C5a receptor 1-driven signaling cascade.

Abstract

Cardiac repair following myocardial infarction is important in regenerating functionally viable myocardium to prevent cardiac death. Previous studies have linked C5aR1 to cardiac regeneration and inflammation. However, C5a receptor-driven responses during the late phases, up to 4 weeks of the infarction insult - a time window that specifically reflects the outcome of the repair process - and the underlying mechanisms are poorly defined. Here, we show that C5ar1, but not C5ar2, deficiency attenuates infarct size following coronary artery ligation-induced myocardial infarction (MI). C5ar1 deficiency limited the deposition of collagen and mitigated cell death in infarcted areas leading to overall improved cardiac function four weeks after MI. While infiltration of neutrophils was reduced in both C5ar1-/- and C5ar2-/- infarcted myocardium 24 h after MI, influx of monocytes after 1 week of MI was reduced only upon C5ar1 deficiency. Subsequent analysis revealed reduced accumulation of myofibroblast, elevated expression of transforming growth factor-beta1 (Tgf-β1) and vascular endothelial growth factor-A (Vegf-A) in C5ar1-/- infarcted hearts. In vitro, exogenous TGF-β1 triggered conversion of fibroblasts into myofibroblasts, which expressed Vegf-A mRNA - an effect that was enhanced upon C5ar1 deficiency. Incubation of C5ar1+/+ or C5ar1-/- endothelial cells (ECs) with supernatants from C5ar1+/+ or C5ar1-/- myofibroblasts respectively, mimicking the in vivo microenvironment in our model, led to significant increase in matrigel tube formation in C5ar1-/- ECs. This was consistent with enhanced neoangiogenesis in C5ar1-/- infarcted hearts. Collectively, our study demonstrates that inhibition of C5aR1 has the potential to improve cardiac function after myocardial infarction.