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Leukocyte-Expressed beta2AR Are Essential for Survival After Acute Myocardial Injury.pdf (6.07 MB)

Leukocyte-Expressed beta2AR Are Essential for Survival After Acute Myocardial Injury.pdf

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journal contribution
posted on 2019-03-08, 13:39 authored by Laurel A. Grisanti, Anna M. Gumpert, Christopher J. Traynham, Joshua E. Gorsky, Ashley A. Repas, Erhe Gao, Rhonda L. Carter, John W. Calvert, Andres Pun Garcia, Borja Ibanez, Joseph E. Rabinowitz, Walter J. Koch, Douglas G. Tilley
Background: Immune cell–mediated inflammation is an essential
process for mounting a repair response after myocardial infarction (MI).
The sympathetic nervous system is known to regulate immune system
function through β-adrenergic receptors (βARs); however, their role in
regulating immune cell responses to acute cardiac injury is unknown.
Methods: Wild-type (WT) mice were irradiated followed by isoformspecific
βAR knockout (βARKO) or WT bone-marrow transplantation (BMT)
and after full reconstitution underwent MI surgery. Survival was monitored
over time, and alterations in immune cell infiltration after MI were examined
through 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 after MI compared with ≈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 vascular cell adhesion
molecule-1 expression, which itself was regulated via β-arrestin–dependent
β2AR signaling. Furthermore, vascular cell adhesion molecule-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
vascular cell adhesion molecule-1 expression. The impairments in splenic
retention and cardiac infiltration of leukocytes after MI were restored to
WT levels via lentiviral-mediated re-expression of β2AR in β2ARKO bone
marrow before transplantation, which also resulted in post-MI survival rates
comparable to those in 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.


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