Deletion of CD28 Co-stimulatory Signals Exacerbates Left Ventricular Remodeling and Increases Cardiac Rupture After Myocardial Infarction

Kubota, Akihiko; Hasegawa, Hiroshi; Tadokoro, Hiroyuki; Hirose, Masao; Kobara, Yuka; Yamada-Inagawa, Tomoko; Takemura, Genzou; Kobayashi, Yoshio; Takano, Hiroyuki

doi:10.1253/circj.cj-16-0327

Cited by 10 publications

(5 citation statements)

References 36 publications

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“…MMP-9 activity increases 3-5 days post-MI and then declines as the inflammatory phase of repair is resolved (4,38). In the mice that died due to cardiac rupture, MK5 haplodeficiency was associated with increased MMP-9 immunoreactivity in the peri-infarct region, but no differences were observed in surviving mice 8 days post-MI.…”

Section: Discussionmentioning

confidence: 97%

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MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair

Nawaito

Sahadevan

Clavet-Lanthier

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts, and MK5 haplodeficiency attenuates the increase in collagen 1-α1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5+/− and wild-type littermate (MK5+/+) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5+/+ and MK5+/− mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5+/+ and LADL-MK5+/− mice. Area at risk did not differ between LADL-MK5+/+ and LADL-MK5+/− hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5+/− hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5+/− hearts compared with LADL-MK5+/+. Although inflammatory cell infiltration was similar in LADL-MK5+/+ and LADL-MK5+/− hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5+/− mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5−/− mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI. NEW & NOTEWORTHY MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.

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Section: Discussionmentioning

confidence: 97%

“…Data shown are the mean Ϯ SE of assessments performed in fibroblasts isolated from 3 different mice. Bar, 250 m. *P Ͻ 0.05; ***P Ͻ 0.001; ****P Ͻ 0.0001. cases of enhanced cardiac rupture (24,54,76), and M1 macrophages release MMP-9 (38,45). However, cardiomyocytes also serve as a source of MMPs in the MI border zone (30).…”

Section: Discussionmentioning

confidence: 99%

MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair

Nawaito

Sahadevan

Clavet-Lanthier

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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“…A hint that costimulatory CD28 signaling might be critical during myocardial healing was provided by a recent publication reporting that CD28 deficient mice show impaired healing due to defective extracellular matrix formation after experimental MI [22]. However, this study did not clarify, if the observed effects were due to disturbed activation of conventional T-cells or, more likely, substantially reduced numbers of natural Tregs in CD28 deficient mice.…”

Section: Plos Onementioning

confidence: 79%

Treatment of mice with a ligand binding blocking anti-CD28 monoclonal antibody improves healing after myocardial infarction

et al. 2020

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Both conventional and regulatory CD4 + T-cells rely on costimulatory signals mediated by cell surface receptors including CD28 for full activation. We showed previously that stimulation of CD4 + Foxp3 + regulatory T-cells by superagonistic anti-CD28 monoclonal antibodies (mAb) improves myocardial healing after experimental myocardial infarction (MI). However, the effect of ligand binding blocking anti-CD28 monoclonal antibodies has not yet been tested in this context. We hypothesize that ligand blocking anti-CD28 mAb treatment might favorably impact on healing after MI by limiting the activation of conventional CD4 + T-cells. Therefore, we studied the therapeutic effect of the recently characterized mAb E18 which blocks ligand binding to CD28 in a mouse permanent coronary ligation model. E18 or an irrelevant control mAb was applied once on day two after myocardial infarction to wildtype mice. Echocardiography was performed on day 7 after MI. E18 treatment improved the survival and reduced the incidence of left ventricular ruptures after experimental myocardial infarction. Accordingly, although we found no difference in infarct size, there was significantly less left ventricular dilation after E18 treatment in surviving animals as determined by echocardiography at day 7 after MI. In sham operated control mice neither antibody had an impact on body weight, survival, and echocardiographic parameters. Mechanistically, compared to control immunoglobulin, E18 treatment reduced the number of CD4 + T-cells and monocytes/macrophages within the infarct and periinfarct zone on day 5. This was accompanied by an upregulation of arginase which is a marker for alternatively differentiated macrophages. The data indicate that CD28-dependent costimulation of CD4 + T-cells impairs myocardial healing and anti-CD28 antibody treatment constitutes a potentially clinically translatable approach to improve the outcome early after MI.

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“…Similarly, the administration of a CD28 antagonist peptide decreased irradiation-induced increase in IL-6 and lowered COX-2 expression and the numbers of macrophages in the small intestine of irradiated mice [37]. The blockade of CD28 signals also exacerbated left ventricular remodeling and increased cardiac rupture after myocardial infarction by prolonging the inflammatory period, which caused a reduction in collagen fibers in infarct scars [38]. These results suggest that CD28 deficiency is effective at ameliorating blast exposure-induced lung inflammation.…”

Section: Discussionmentioning

confidence: 99%

CD28 Deficiency Ameliorates Blast Exposure-Induced Lung Inflammation, Oxidative Stress, Apoptosis, and T Cell Accumulation in the Lungs via the PI3K/Akt/FoxO1 Signaling Pathway

Liu

Tong

et al. 2019

Oxidative Medicine and Cellular Longevity

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Although CD28 is associated with the expression of inflammatory mediators, apoptosis-related protein, immunosuppression, and tumorigenesis, the effects of CD28 deficiency on blast exposure-induced lung injury have not been investigated. In this study, we have explored the effects of CD28 on blast exposure-induced lung injury and studied its potential molecular mechanisms. A mouse model of blast exposure-induced acute lung injury was established. Sixty C57BL/6 wild-type (WT) and CD28 knockout (CD28-/-) mice were randomly divided into control or model groups. Lung tissue samples were collected 24 h and 48 h after blast injury. Histopathological changes and the expressions of inflammatory-related proteins were detected by hematoxylin-eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis and oxidative stress were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS). Inflammation, apoptosis, oxidative stress, and related pathway protein expression were studied by western blotting. In addition, the levels of CD3 and CD28 proteins were measured by flow cytometry. In the current study, we found that CD28 deficiency significantly inhibited blast exposure-induced increases in the lung weight/body weight ratio and wet weight/dry weight ratio; decreased the infiltration of CD44+ leukocytes, CD163+ macrophages, and CD3+ T cells into the lungs; reduced the expressions of proinflammatory cytokines including IL-1β, TNF-α, and IL-6; and markedly increased IL-10 expression. CD28 deficiency also significantly attenuated blast exposure-induced ROS, MDA5, and IREα expressions; increased SOD-1 expression; lowered the number of apoptotic cells and Bax, Caspase-3, and active Caspase-8 expressions; and increased Bcl-2 expression. Additionally, CD28 deficiency significantly ameliorated blast exposure-induced increases of p-PI3K and p-Akt and ameliorated the decrease in the p-FoxO1 expression. Our results suggest that CD28 deficiency has a protective effect on blast exposure-induced lung injury, which might be associated with the PI3K/Akt/FoxO1 signaling pathway.

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Deletion of CD28 Co-stimulatory Signals Exacerbates Left Ventricular Remodeling and Increases Cardiac Rupture After Myocardial Infarction

Cited by 10 publications

References 36 publications

MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair

MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair

Treatment of mice with a ligand binding blocking anti-CD28 monoclonal antibody improves healing after myocardial infarction

CD28 Deficiency Ameliorates Blast Exposure-Induced Lung Inflammation, Oxidative Stress, Apoptosis, and T Cell Accumulation in the Lungs via the PI3K/Akt/FoxO1 Signaling Pathway

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