Leukocyte-Expressed β2-Adrenergic Receptors are Essential for Survival Following Acute Myocardial Injury
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.
- Received March 1, 2016.
- Revision received April 20, 2016.
- Accepted May 17, 2016.