Prior beta blocker treatment decreases leukocyte responsiveness to injury

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

doi:10.1172/jci.insight.99485

Cited by 25 publications

(23 citation statements)

References 32 publications

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“…β 2 -AR agonists cause a similar reduction in TNF-α production in mononuclear cells of the peripheral blood from diabetic rats [64]. Furthermore, the chronic use of β 2 -ARselective and nonselective blockers in mice impairs the recruitment of leukocytes to the injured heart and reduces survival [65].…”

Section: Discussionmentioning

confidence: 97%

Stress-induced Differential Gene Expression in Cardiac Tissue

Carvalho

Cordeiro

Rodrigues

et al. 2021

Preprint

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The stress response is adaptive and aims to guarantee survival. However, the persistence of a stressor can culminate in pathology. Catecholamines released as part of the stress response over activate beta adrenoceptors (β-AR) in the heart. Whether and how stress affects the expression of components of the intracellular environment in the heart is still, however, unknown. This paper used microarray to analyze the gene expression in the left ventricle wall of rats submitted to foot shock stress, treated or not treated with the selective β2-AR antagonist ICI118,551 (ICI), compared to those of non-stressed rats also treated or not with ICI, respectively. The main findings were that stress induces changes in gene expression in the heart and that β2-AR plays a role in this process. The vast majority of genes disregulated by stress were exclusive for only one of the comparisons, indicating that, in the same stressful situation, the profile of gene expression in the heart is substantially different when the β2-AR is active or when it is blocked. Stress induced alterations in the expression of such a large number of genes seems to be an adaptive reaction, aimed at sustaining heart function and protecting cardiomyocytes from apoptosis.

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Section: Discussionmentioning

confidence: 97%

Stress-induced Differential Gene Expression in Cardiac Tissue

Carvalho

Cordeiro

Rodrigues

et al. 2021

Preprint

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“…β2-ARs have been described throughout the peripheral and central nervous system. 48 – 50 In peripheral tissue, β2-ARs have been localized in keratinocytes, 32 , 51 myeloid cells including macrophage and dendritic cells, 52 , 53 satellite glial cells 25 and sensory neurons. 30 , 54 – 56 In the spinal cord, we observed β2-AR-IR on subpopulations of neurons, microglia but not astrocytes in the normal and incision rats.…”

Section: Discussionmentioning

confidence: 99%

Systemic administration of a β2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity

et al. 2021

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Beta 2 adrenergic receptor (β2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of β2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the β2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of β2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined β2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of β2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of β2-AR agonists to models of surgical injury.

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“…β-blockers have been used successfully for decades to treat several pathologies, including hypertension, congestive heart failure, and post-MI dysfunction [21]. Moreover, chronic β-blocker treatment could alter baseline leukocyte characteristics that decrease their responsiveness to acute injury, and it means prior β-blockade may act to reduce the severity of innate immune responses [22]. Since β1AA is a weak agonist of β1AR, its accumulation might lead to the opposite effect of the blockers.…”

Section: Discussionmentioning

confidence: 99%

β1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway

Shi

Liu

Zhang

et al. 2020

BMC Cardiovasc Disord

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Background: Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that β1 adrenoceptor antibodies (β1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and β1AA, including the mechanism of β1AA leading to PPCM. Methods: We extracted the β1AA from the postpartum Wistar rats that were injected by the antigen peptide segment of the β1 adrenoceptor to produce PPCM. We tested the effects of β1AA on H9C2 cell line by CCK-8, LDH, TUNEL, SA-ELISA, qRT-PCR, and western blot methods. Furthermore, PGC-1α was overexpressed to rescue the effect of β1AA on H9C2 cells. Results: We found that the extracted β1AA induced apoptosis of cardiac myocytes of H9C2 cell line. Moreover, the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is a master regulator of mitochondrial metabolism, and its downstream transcript vascular endothelial growth factor (VEGF) got decreased in H9C2 cells after β1AA treatment. In addition, the effect of β1AA could be inhibited by atenolol, the antagonist of β1 adrenoceptors (β1AR) and imitated by isoprenaline, the agonist of β1AR. Furthermore, overexpression of PGC-1α in the H9C2 cells rescued the apoptosis of cells and inhibitory expression of VEGF induced by β1AA. Conclusions: Our results suggest that the symptoms of PPCM due to myocardial cell apoptosis induced by β1AA inhibiting the PGC-1α-related pathway impairs mitochondrial energy metabolism. Therefore, our results uncover a previously unknown role of the β1AA pathway in the etiology of PPCM and provide a novel potential target for the treatment of PPCM.

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Prior beta blocker treatment decreases leukocyte responsiveness to injury

Cited by 25 publications

References 32 publications

Stress-induced Differential Gene Expression in Cardiac Tissue

Stress-induced Differential Gene Expression in Cardiac Tissue

Systemic administration of a β2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity

β1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway

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