Leukocyte-Expressed β ₂ -Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury

Abstract

Background Immune cell-mediated inflammation is an essential process for mounting a repair response following myocardial infarction (MI). The sympathetic nervous system is known to regulate immune system function through β-adrenergic receptors (βAR), however their role in regulating immune cell responses to acute cardiac injury is unknown. Methods Wild-type (WT) mice were irradiated followed by isoform-specific βARKO or WT bone-marrow transplantation (BMT) and after full reconstitution underwent myocardial infarction (MI) surgery. Survival was monitored over time and alterations in immune cell infiltration following MI were examined using immunohistochemistry. Alterations in splenic function were identified through the investigation of altered adhesion receptor expression. Results β2ARKO BMT mice displayed 100% mortality resulting from cardiac rupture within 12 days post-MI compared to ~20% mortality in WT BMT mice. β2ARKO BMT mice displayed severely reduced post-MI cardiac infiltration of leukocytes with reciprocally enhanced splenic retention of the same immune cell populations. Splenic retention of the leukocytes was associated with an increase in VCAM-1 expression, which was itself regulated via β-arrestin-dependent β2AR signaling. Further, VCAM-1 expression in both mouse and human macrophages was sensitive to β2AR activity, and spleens from human tissue donors treated with β-blocker showed enhanced VCAM1 expression. The impairments in splenic retention and cardiac infiltration of leukocytes following MI were restored to WT levels via lentiviral-mediated re-expression of β2AR in β2ARKO BM prior to transplantation, which also resulted in post-MI survival rates comparable to WT BMT mice. Conclusions Immune cell-expressed β2AR plays an essential role in regulating the early inflammatory repair response to acute myocardial injury by facilitating cardiac leukocyte infiltration.

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

“…Sympathetic activity is known to regulate inflammation, with β2AR being the predominant adrenergic receptor subtype involved in immunomodulation (4-6). Recent findings from our laboratory have identified a critical role for hematopoietically expressed β2AR in survival following MI, wherein a lack of β2AR on immune cells resulted in decreased leukocyte infiltration to the heart, failed scar formation, and cardiac rupture (7). Although splenic retention of leukocytes played a role in the phenotype, whether the diminished leukocyte recruitment to the injured heart in the absence of immune cell-expressed β2AR involved an alteration in the response to promigratory chemokines was not determined.…”

“…We recently observed decreased leukocyte infiltration into the hearts of chimeric mice lacking immune cellexpressed β2AR following MI (7). Chemokines produced following injury are important for recruitment of immune cells, through their action on chemokine receptors.…”

“…Based on our in vitro assessment of the impact of β2AR deletion on CCR2 expression and BM cell migration, we sought to determine whether CCR2 inhibition in vivo, either pharmacologically or genetically, could recapitulate the impaired leukocyte post-MI infiltration phenotype observed in β2ARKO BMT mice (7). To assess this, WT mice underwent sham or MI surgery followed by daily injections with vehicle or CCR2 antagonist (2 mg·kg −1 ·d −1 ), or underwent irradiation and received WT, β2ARKO, or CCR2KO BM 1 mo before surgery (Fig.…”

“…Recently, we showed that immune cell-expressed β2AR is required for leukocyte recruitment to the heart following acute myocardial infarction (MI), without which the heart cannot mount a repair response, ultimately undergoing rupture (7). Because chemokine receptors play a critical role in migration and infiltration of leukocyte populations, we hypothesized that immune cell-expressed chemokine receptor activity and/or expression may be altered in the absence of β2AR, thereby impairing leukocyte migration to the injured heart.…”

Impact of paroxetine on proximal β-adrenergic receptor signaling

“…β-adrenergic receptor (βAR) signaling regulates a large repertoire of functions throughout the body, including cardiac contractility, vascular relaxation, immune cell function and central effects 1–3 . βAR desensitization has long been recognized as a contributing factor to the progression of various disease states and is largely mediated via regulation by G protein-coupled receptor kinase (GRK)-dependent processes 4, 5 .…”