期刊
CIRCULATION
卷 134, 期 2, 页码 153-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.116.022304
关键词
immune system; inflammation; leukocytes; myocardial infarction
资金
- National Institutes of Health [HL105414, HL091799, HL085503, HL098481]
- American Heart Association
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 beta-adrenergic receptors (beta ARs); however, their role in regulating immune cell responses to acute cardiac injury is unknown. Methods: Wild-type (WT) mice were irradiated followed by isoformspecific beta AR knockout (beta ARKO) 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: beta(2) ARKO BMT mice displayed 100% mortality resulting from cardiac rupture within 12 days after MI compared with approximate to 20% mortality in WT BMT mice. beta(2)ARKO BMT mice displayed severely reduced postMI 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 beta-arrestin-dependent beta(2)AR signaling. Furthermore, vascular cell adhesion molecule-1 expression in both mouse and human macrophages was sensitive to beta(2)AR activity, and spleens from human tissue donors treated with beta-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 beta(2)AR in beta(2)ARKO bone marrow before transplantation, which also resulted in post-MI survival rates comparable to those in WT BMT mice. Conclusions: Immune cell-expressed beta(2)AR plays an essential role in regulating the early inflammatory repair response to acute myocardial injury by facilitating cardiac leukocyte infiltration.
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