Loss of cyclic GMP-AMP synthase function significantly improved early survival, diminished pathological remodeling, and promoted reparative macrophage transformation after myocardial infarction.
Does cyclic GMP-AMP synthase loss of function improve survival and cardiac repair after myocardial infarction in animal models?
The cGAS-STING pathway acts as a pattern recognition receptor during cardiac ischemia, and its inhibition promotes reparative macrophage transformation and improves post-injury cardiac repair.
BACKGROUND: Myocardium irreversibly injured by ischemic stress must be efficiently repaired to maintain tissue integrity and contractile performance. Macrophages play critical roles in this process. These cells transform across a spectrum of phenotypes to accomplish diverse functions ranging from mediating the initial inflammatory responses that clear damaged tissue to subsequent reparative functions that help rebuild replacement tissue. Although macrophage transformation is crucial to myocardial repair, events governing this transformation are poorly understood. METHODS: Here, we set out to determine whether innate immune responses triggered by cytoplasmic DNA play a role. RESULTS: We report that ischemic myocardial injury, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase and promotes the transformation of macrophages to a reparative phenotype, which results in enhanced repair and improved hemodynamic performance. CONCLUSIONS: These results reveal, for the first time, that the cytosolic DNA receptor cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because modulators of this pathway are currently in clinical use, our findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.
Cao et al. (Thu,) conducted a other in Myocardial ischemic injury. Cyclic GMP-AMP synthase loss of function was evaluated on Early survival and pathological remodeling after myocardial infarction. Loss of cyclic GMP-AMP synthase function significantly improved early survival, diminished pathological remodeling, and promoted reparative macrophage transformation after myocardial infarction.