Activation of β2-Adrenergic Receptor Alleviates Viral Myocarditis by Regulating Energy Metabolism in Monocyte-derived Macrophages via the AMPK Pathway.

Acute viral myocarditis (AVM) is a leading cause of sudden cardiac death in young individuals, and currently, there are no effective targeted clinical treatments. The role and underlying mechanisms of β2-adrenergic receptors (β2-AR) in the pathogenesis of viral myocarditis remain inadequately understood. We found that β2-AR expression reduced in monocyte-derived macrophage (MoMFs). Activation of β2-AR significantly alleviated inflammatory responses, reduced fibrosis, and improved cardiac function in AVM mice. The protective effects of activating β2-AR on AVMs were mediated by reducing MoMFs infiltration into the heart, promoting M2 phenotype, decreasing the circulating Ly6C(high) proinflammatory monocytes, and increasing splenic Ly6C monocyte retention. The combination of macrophage depletion with activating β2-AR did not exhibit synergistic effects on reducing cardiac pathological scores or fibrosis. Mechanistically, metabolomic and transcriptomic analyses of heart tissues from AVM mice and bone marrow-derived macrophages (BMDMs) revealed that activating β2-AR affected energy metabolism. Specifically, activating β2-AR reduced the level of intracellular reactive oxygen species and increased energy metabolism via activated the AMP-activated protein kinase (AMPK) pathway in BMDMs. Hence, activating β2-AR may protects against AVM by regulating MoMF infiltration and preventing M1 polarization through the AMPK pathway, thereby maintaining mitochondrial balance and enhancing energy metabolism.