Adrenergic receptors on immune cells in cardiovascular disease: signaling plasticity, biased agonism, and therapeutic opportunities

Figures

• 

  Figure 1. Overview of the sympathetic–immune–cardiovascular axis in cardiovascular disease. Sympathetic nerve terminals release norepinephrine (NE) locally within cardiovascular tissues, whereas the adrenal medulla releases epinephrine (Epi) and NE into the circulation, generating endocrine catecholamine signals. These catecholamines engage adrenergic receptors (ARs) expressed on major vascular targets—endothelial cells, fibroblasts, cardiomyocytes, and vascular smooth muscle cells—as well as on immune cell targets including macrophages, dendritic cells, neutrophils, and lymphocytes. By acting on both vascular and immune compartments, adrenergic signaling integrates neurohumoral stress with inflammation and remodeling across the disease contexts reviewed here, including systemic hypertension (HTN), pulmonary HTN, atherosclerosis, heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), myocarditis, and myocardial infarction.

• 

  Figure 2. Adrenergic receptor subtypes and core signaling/regulatory logic relevant to cardiovascular and immune responses. Adrenergic receptors (ARs) are class A G protein–coupled receptors comprising three families—α1 (α1A/α1B/α1D), α2 (α2A/α2B/α2C), and β (β1/β2/β3)—that translate catecholamine cues into subtype-biased intracellular programs. α1ARs couple predominantly to Gαq/11 to activate phospholipase C (PLC), generating IP3 and DAG, increasing intracellular Ca2+, and activating protein kinase C (PKC). α2ARs preferentially couple to Gαi/o to inhibit adenylyl cyclase and reduce cAMP-dependent signaling, while released Gβγ subunits can engage additional downstream effectors. βARs classically couple to Gαs to stimulate adenylyl cyclase, increase cAMP, and activate protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC); depending on cellular context and receptor phosphorylation state, βARs—particularly β2AR—can also exhibit coupling plasticity, including switching from Gs to Gi and redirecting signaling toward alternative kinase pathways. Across AR families, receptor activation promotes G protein–coupled receptor kinase (GRK)-mediated phosphorylation, β-arrestin…

• 

  Figure 3. Shared immune effector pathways linking acute injury to chronic inflammatory remodeling across cardiovascular disease contexts. The schematic contrasts acute injury (left) and chronic injury (right) programs across the disease settings discussed in this review—myocardial infarction, atherosclerosis, hypertension, and heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). In acute injury (myocardial infarction), sterile damage-associated molecular patterns (DAMPs) and early endothelial activation promote rapid recruitment of neutrophils and inflammatory monocytes; neutrophil reactive oxygen species (ROS), proteases, matrix metalloproteinases (MMPs), and neutrophil extracellular trap (NET)-associated programs amplify early inflammation and shape subsequent leukocyte waves. Recruited monocytes differentiate into macrophages that initially adopt inflammatory “M1-like” outputs (e.g., TNF, IL-1β, IL-6) and later transition toward pro-resolving/repair “M2-like” states (e.g., IL-10, TGF-β) supported by efferocytosis and tissue repair programs; in parallel, antigen presentation supports adaptive responses (Th1/Th17/Th2 and regulatory T cell…