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Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury.

ABSTRACT: The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that CLEC4E expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. CLEC4E expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating leukocytes in the ischemic heart. Loss of Clec4e signaling is associated with reduced acute cardiac injury, neutrophil infiltration, and infarct size. Reduced myocardial injury in Clec4e ^-/- translates into significantly improved LV structural and functional remodeling at 4 weeks' follow-up. The early transcriptome of LV tissue from Clec4e ^-/- mice versus wild-type mice reveals significant upregulation of transcripts involved in myocardial metabolism, radical scavenging, angiogenesis, and extracellular matrix organization. Therefore, targeting CLEC4E in the early phase of ischemia-reperfusion injury is a promising therapeutic strategy to modulate myocardial inflammation and enhance repair after ischemia-reperfusion injury.

SUBMITTER: Veltman D

PROVIDER: S-EPMC8385568 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury.

Veltman Denise D Wu Ming M Pokreisz Peter P Claus Piet P Gillijns Hilde H Caluwé Ellen E Vanhaverbeke Maarten M Gsell Willy W Himmelreich Uwe U Sinnaeve Peter R PR Janssens Stefan P SP

JACC. Basic to translational science 20210823 8

The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that <i>CLEC4E</i> expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. <i>CLEC4E</i> expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating l ...[more]

PMID: 34466750

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Project description:Ischemia-reperfusion (I/R) injury is an unavoidable injury that occurs during revascularization procedures. In the previous study, we reported that fisetin is a natural flavonoid that attenuates I/R injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction. Though fisetin is reported as a GSK3β inhibitor, it remains unclear whether it attenuates myocardial ischemia by activating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, thereby inhibiting the downstream GSK3β, or by directly interacting with GSK3β while rendering its cardioprotection. In this study, the research team investigates the possible mechanism of action of fisetin while rendering its cardioprotective effect against myocardial I/R injury in rats. For this investigation, the team utilized two myocardial I/R models: Ligation of the left anterior descending artery and Langendorff isolated heart perfusion system. The latter has no neurohormonal influences. The PI3K inhibitor (Wortmannin, 0.015 mg/kg), GSK3β inhibitor (SB216763, 0.7 mg/kg), and fisetin (20 mg/kg) were administered intraperitoneally before inducing myocardial I/R. The result of this study reveals that the administration of fisetin decreases the myocardial infarct size, apoptosis, lactate dehydrogenase, and creatine kinase in serum\perfusate of the rat hearts subjected to I/R. However, the inhibition of PI3K with Wortmannin significantly reduced the cardioprotective effect of fisetin both in the ex vivo and vivo models. The administration of GSK3β inhibitor after the administration of fisetin and Wortmannin, re-establishing the cardioprotection, indicates the major role of PI3K in fisetin action. Changes in myocardial oxidative stress (level) and mitochondrial functional preservation of interfibrillar and subsarcolemmal mitochondria support the above findings. Hence, the team here reports that fisetin conferred its cardioprotection against I/R injury by activating the PI3K/Akt/GSK3β signaling pathway in rat hearts.

Project description:BackgroundMyocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood.MethodsIn vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 μg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment.ResultsIn the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response ( P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis ( P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 μM DEX pretreatment improved cell viability ( P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis ( P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic.ConclusionsDEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro.

Dataset Information

Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury.

Publications

Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury.

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