Prior beta blocker treatment decreases leukocyte responsiveness to injury
Laurel A. Grisanti, Claudio de Lucia, Toby P. Thomas, Aron Stark, John T. Strony, Valerie D. Myers, Remus Beretta, Daohai Yu, Celestino Sardu, Raffaele Marfella, Erhe Gao, Steven R. Houser, Walter J. Koch, Eman A. Hamad, Douglas G. Tilley
Laurel A. Grisanti, Claudio de Lucia, Toby P. Thomas, Aron Stark, John T. Strony, Valerie D. Myers, Remus Beretta, Daohai Yu, Celestino Sardu, Raffaele Marfella, Erhe Gao, Steven R. Houser, Walter J. Koch, Eman A. Hamad, Douglas G. Tilley
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Research Article Cardiology Immunology

Prior beta blocker treatment decreases leukocyte responsiveness to injury

Abstract

Following injury, leukocytes are released from hematopoietic organs and migrate to the site of damage to regulate tissue inflammation and repair; however, leukocytes lacking β2-adrenergic receptor (β2-AR) expression have marked impairments in these processes. Beta blockade is a common strategy for the treatment of many cardiovascular etiologies; therefore, the objective of our study was to assess the impact of prior beta blocker treatment on baseline leukocyte parameters and their responsiveness to acute injury. In a temporal and β-adrenergic receptor isoform–dependent manner, chronic beta blocker infusion increased splenic vascular cell adhesion molecule 1 expression and leukocyte accumulation (monocytes/macrophages, mast cells, and neutrophils) and decreased chemokine receptor 2 (CCR2) expression and migration of bone marrow and peripheral blood leukocytes (PBLs) to, as well as infiltration into, the heart following acute cardiac injury. Further, CCR2 expression and migratory responsiveness were significantly reduced in the PBLs of patients receiving beta blocker therapy compared with beta blocker–naive patients. These results highlight the ability of chronic beta blocker treatment to alter baseline leukocyte characteristics that decrease leukocytes’ responsiveness to acute injury and suggest that prior beta blockade may act to reduce the severity of innate immune responses.

Authors

Laurel A. Grisanti, Claudio de Lucia, Toby P. Thomas, Aron Stark, John T. Strony, Valerie D. Myers, Remus Beretta, Daohai Yu, Celestino Sardu, Raffaele Marfella, Erhe Gao, Steven R. Houser, Walter J. Koch, Eman A. Hamad, Douglas G. Tilley

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Figure 6

Chronic beta blocker infusion before MI does not affect infarct size but does alter survival and CCR2 expression.

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Chronic beta blocker infusion before MI does not affect infarct size but...
(A) Representative Masson’s trichrome staining of infarcted hearts, 4 and 21 days after MI, from mice treated for 2 weeks with Veh, ICI, Carv, Met Low, or Met High before surgery. For 4 days: Veh (n = 11), ICI (n = 7), Carv (n = 6), Met Low (n = 5), or Met High (n = 4); for 21 days: Veh (n = 8), ICI (n = 2), Carv (n = 5), Met Low (n = 8), or Met High (n = 5). Scale bar: 2 mm. (B and C) Quantification of infarct lengths from A. (D) Survival of mice that had received infusion of Veh, ICI, Carv, Met Low, or Met High for 2 weeks before sham or MI surgery, as monitored daily for 21 days after MI. Log-rank test: *P < 0.05, and †P < 0.01 versus Veh MI. Starting n = 10 for Veh-treated sham group; n = 5 for ICI sham; n = 4 for Carv sham, Met High sham, and Met Low sham; n = 26 for Veh MI; and n = 13 for ICI MI, Carv MI, Met High MI, and Met Low MI. (E) RT-pPCR was used to quantify BMC CCR2 expression from sham-treated and 4-day post-MI mice that were administered Veh, ICI, Carv, Met Low, or Met High for 2 weeks before surgery. Overall Kruskal-Wallis test P value: P < 0.0001. n = 8 for Veh sham, n = 11 for Veh MI, n = 7 for ICI sham, n = 7 for ICI MI, n = 4 for Carv sham, n = 6 for Carv MI, n = 4 for Met Low sham, n = 5 for Met Low MI, n = 3 for Met High sham, and n = 4 for Met High MI. Results of exact Wilcoxon rank-sum tests with multiple-comparison adjustment — 13 comparisons: sham beta blockers versus MI beta blockers, sham beta blockers versus sham Veh, and MI beta blockers versus MI Veh — are indicated in scatter dot plots. *P < 0.05, and †P < 0.01.