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.