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Carnosine Supplementation Enhances Post Ischemic Hind Limb Revascularization.

ABSTRACT: High (millimolar) concentrations of the histidine containing dipeptide - carnosine (?-alanine-L-histidine) are present in the skeletal muscle. The dipeptide has been shown to buffer intracellular pH, chelate transition metals, and scavenge lipid peroxidation products; however, its role in protecting against tissue injury remains unclear. In this study, we tested the hypothesis that carnosine protects against post ischemia by augmenting HIF-1? angiogenic signaling by Fe²⁺ chelation. We found that wild type (WT) C57BL/6 mice, subjected to hind limb ischemia (HLI) and supplemented with carnosine (1g/L) in drinking water, had improved blood flow recovery and limb function, enhanced revascularization and regeneration of myocytes compared with HLI mice placed on water alone. Carnosine supplementation enhanced the bioavailability of carnosine in the ischemic limb, which was accompanied by increased expression of proton-coupled oligopeptide transporters. Consistent with our hypothesis, carnosine supplementation augmented HIF-1? and VEGF expression in the ischemic limb and the mobilization of proangiogenic Flk-1⁺/Sca-1⁺ cells into circulation. Pretreatment of murine myoblast (C2C12) cells with octyl-D-carnosine or carnosine enhanced HIF-1? protein expression, VEGF mRNA levels and VEGF release under hypoxic conditions. Similarly pretreatment of WT C57/Bl6 mice with carnosine showed enhanced blood flow in the ischemic limb following HLI surgery. In contrast, pretreatment of hypoxic C2C12 cells with methylcarcinine, a carnosine analog, lacking Fe²⁺ chelating capacity, had no effect on HIF-1? levels and VEGF release. Collectively, these data suggest that carnosine promotes post ischemic revascularization via augmentation of pro-angiogenic HIF-1?/VEGF signaling, possibly by Fe²⁺ chelation.

SUBMITTER: Boakye AA

PROVIDER: S-EPMC6614208 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Carnosine Supplementation Enhances Post Ischemic Hind Limb Revascularization.

Boakye Adjoa A AA Zhang Deqing D Guo Luping L Zheng Yuting Y Hoetker David D Zhao Jingjing J Posa Dheeraj Kumar DK Ng Chin K CK Zheng Huaiyu H Kumar Amit A Kumar Vijay V Wempe Michael F MF Bhatnagar Aruni A Conklin Daniel J DJ Baba Shahid P SP

Frontiers in physiology 20190702

High (millimolar) concentrations of the histidine containing dipeptide - carnosine (β-alanine-L-histidine) are present in the skeletal muscle. The dipeptide has been shown to buffer intracellular pH, chelate transition metals, and scavenge lipid peroxidation products; however, its role in protecting against tissue injury remains unclear. In this study, we tested the hypothesis that carnosine protects against post ischemia by augmenting HIF-1α angiogenic signaling by Fe<sup>2+</sup> chelation. We ...[more]

PMID: 31312142

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Project description:Despite intensive investigation, how DNA methylation influences endothelial function remains poorly understood. We used methyl-CpG-binding domain protein 2 (MBD2), an interpreter for DNA methylome-encoded information, to dissect the impact of DNA methylation on endothelial function in both physiological and pathophysiological states.Human umbilical vein endothelial cells under normal conditions express moderate levels of MBD2, but knockdown of MBD2 by siRNA significantly enhanced angiogenesis and provided protection against H(2)O(2)-induced apoptosis. Remarkably, Mbd2(-/-) mice were protected against hind-limb ischemia evidenced by the significant improvement in perfusion recovery, along with increased capillary and arteriole formation. Loss of MBD2 activated endothelial survival and proangiogenic signals downstream of vascular endothelial growth factor signaling characterized by an increase in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor 2 expression, along with enhanced extracellular signal-regulated kinase 1/2 activation and BCL-2 expression. Mechanistic studies confirmed the methylation of CpG elements in the eNOS and vascular endothelial growth factor receptor 2 promoter. MBD2 binds to these methylated CpG elements and suppresses eNOS promoter activity. On ischemic insult, key endothelial genes such as eNOS and vascular endothelial growth factor receptor 2 undergo a DNA methylation turnover, and MBD2 interprets the changes of DNA methylation to suppress their expressions. Moreover, MBD2 modulation of eNOS expression is likely confined to endothelial cells because nonendothelial cells such as splenocytes fail to express eNOS after loss of MBD2.We provided direct evidence supporting that DNA methylation regulates endothelial function, which forms the molecular basis for understanding how environmental insults (epigenetic factor) affect the genome to modify disease susceptibility. Because MBD2 itself does not affect the methylation of DNA and is dispensable for normal physiology in mice, it could be a viable epigenetic target for modulating endothelial function in disease states.

Project description:IntroductionIntravenous thrombolysis (IVT) and mechanical thrombectomy (MT) in women with ischemic stroke (IS) during pregnancy/post-partum is challenging, and recent guidelines claimed for additional information to better argue its effectiveness and safety. This observational national study aimed to describe characteristics, rates and outcomes of pregnant/post-partum women receiving acute revascularization therapy for IS compared to their non-pregnant counterparts, and pregnant women with IS not receiving such therapy.Patients and methodsIn this cross-sectional study, all women aged 15-49 years hospitalized in France for IS between 2012 and 2018 were retrieved from the French hospital discharge databases. Pregnant or post-partum (⩽6 weeks after delivery) women were identified. Data about patients' characteristics, risk factors, revascularization therapy, delivery, post-stroke survival, and recurrent vascular events during follow-up were recorded.ResultsOver the study period, 382 women with pregnancy-related IS were registered. Among them, 7.3% (n = 28) received a revascularization therapy, including nine cases during pregnancy, one the same day as delivery, and 18 during the post-partum period, compared with 8.5% (n = 1285) in women with non-pregnancy-related IS (n = 15,084). Treated pregnant/post-partum women had more severe IS than not-treated pregnant/post-partum. Compared with treated not-pregnant women, they were younger, but did not differ regarding other characteristics including stroke severity. There were no differences in systemic or intracranial hemorrhages or in the length of hospital stay between pregnant/post-partum women compared with treated not-pregnant women. All women receiving revascularization during pregnancy had a live baby. After a mean follow-up of 4.3 years, all pregnant/post-partum women were alive, one had recurrent IS and none had other vascular events.Discussion and conclusionOnly a few women with pregnancy-related IS were treated with acute revascularization therapy, but this was proportionately similar to their non-pregnant counterparts, from whom they did not differed regarding characteristics, survival, and risk of recurrent events. These findings suggest that stroke physicians applied treatment strategies of IS in a similar way regardless of pregnancy in France, and this attitude was an anticipation but consistent with the recently published guidelines on the topic.

Dataset Information

Carnosine Supplementation Enhances Post Ischemic Hind Limb Revascularization.

Publications

Carnosine Supplementation Enhances Post Ischemic Hind Limb Revascularization.

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