Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1

Marfella, Raffaele; D’Amico, Michele; Filippo, Clara Di; Piegari, Elena; Nappo, Francesco; Esposito, Katherine; Berrino, Liberato; Rossi, Francesco; Giugliano, Dario

doi:10.1007/s00125-002-0882-x

Cited by 148 publications

(60 citation statements)

References 41 publications

(44 reference statements)

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“…Previous studies using animal models have shown that diabetes induces upregulation of HIF-1a expression in isolated rat hearts [22], rat peripheral nerves [42], mouse kidney mesangial cells [23] and mouse glomeruli [43]. Studies based on samples from diabetic patients have reported increased HIF-1a expression in human preretinal membranes [44,45] and mesangial cells [23].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that VEGF causes BBB disruption and increases BBB permeability [19,20], possibly by altering TJ proteins such as ZO-1 [9,15,21] and occludin [9,21]. High glucose has been reported to upregulate HIF-1 activity in isolated hearts of rats [22], mouse kidney mesangial cells [23], human mesangial cells [23], etc. However, it is not known if HIF-1 is induced in and involved in permeability dysfunction of brain endothelial cells exposed to high glucose.…”

Section: Introductionmentioning

confidence: 99%

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HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells

Yan

Zhang

Shi

2011

Cell. Mol. Life Sci.

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Experimental evidence from human patients and animal models of diabetes has demonstrated that hyperglycemia increases blood-brain barrier (BBB) permeability, which is associated with increased risk of neurological dysfunction. However, the mechanism underlying high glucose-induced BBB disruption is not understood. Here we investigated the role of hypoxia-inducible factor-1 (HIF-1) in high glucose-induced endothelial permeability in vitro using mouse brain microvascular endothelial cells (b.End3). Our results demonstrated that high glucose (30 mM) upregulated the protein level of HIF-1α, the regulatable subunit of HIF-1, and increased the transcriptional activity of HIF-1 in the endothelial cells. At the same time, high glucose increased the paracellular permeability associated with diminished expression and disrupted continuity of tight junction proteins occludin and zona occludens protein-1 (ZO-1) of the endothelial cells. Upregulating HIF-1 activity by cobalt chloride increased the paracellular permeability of the endothelial cells exposed to normal glucose (5.5 mM). In contrast, downregulating HIF-1 activity by HIF-1α inhibitors and HIF-1α specific siRNA ameliorated the increased paracellular permeability and the alterations of distribution pattern of occludin and ZO-1 induced by high glucose. In addition, high glucose increased expression of vascular endothelial growth factor (VEGF), a downstream gene of HIF-1. Inhibiting VEGF improved the expression pattern of occludin and ZO-1, and attenuated the endothelial leakage. Furthermore, key results were confirmed in human brain microvascular endothelial cells. These results strongly indicate that HIF-1 plays an important role in high glucose-induced BBB dysfunction. The results will help us understand the molecular mechanisms involved in hyperglycemia-induced BBB dysfunction and neurological outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells

Yan

Zhang

Shi

2011

Cell. Mol. Life Sci.

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“…In the STZ-induced diabetic rats subjected to I/R injury, hyperglycemia, an independent risk factor, worsens cardiac performance, cell survival, and tissue injury following myocardial I/R via increased oxidant production and reduced antioxidant defenses [2,3,59]. In our study, CAPA ameliorated the I/R injury, but this protective effect disappeared when the –OH functional groups were substituted with methoxyl groups, and the antioxidant activity of CAPA may contribute to the protective effect on the I/R injury and cardiac dysfunction in diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, the infarct size of the heart is increased in streptozotocin (STZ)-induced type 1 diabetic rats under ischemia/reperfusion (I/R) injury [2,3]. …”

Section: Introductionmentioning

confidence: 99%

Caffeic acid phenethyl amide ameliorates ischemia/reperfusion injury and cardiac dysfunction in streptozotocin-induced diabetic rats

Lee

Chen

et al. 2014

Cardiovasc Diabetol

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BackgroundCaffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats.MethodsType 1 diabetes mellitus was induced in Sprague–Dawley rats by a single intravenous injection of 60 mg/kg STZ. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. CAPA was pretreated intraperitoneally 30 minutes before reperfusion. An analog devoid of the antioxidant property of CAPA, dimethoxyl CAPA (dmCAPA), and a nitric oxide synthase (NOS) inhibitor (Nω-nitro-l-arginine methyl ester [l-NAME]) were used to evaluate the mechanism involved in the reduction of the infarct size following CAPA-treatment. Finally, the cardioprotective effect of chronic treatment of CAPA was analyzed in diabetic rats.ResultsCompared to the control group, CAPA administration (3 and 15 mg/kg) significantly reduced the myocardial infarct size after I/R, while dmCAPA (15 mg/kg) had no cardioprotective effect. Interestingly, pretreatment with a NOS inhibitor, (l-NAME, 3 mg/kg) eliminated the effect of CAPA on myocardial infarction. Additionally, a 4-week CAPA treatment (1 mg/kg, orally, once daily) started 4 weeks after STZ-induction could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals.ConclusionsCAPA, which is structurally similar to CAPE, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals.

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“…2). Indeed, high glucose is one of only a few non-hypoxic factors that can increase HIF-1α mRNA/protein in various cell types [101], including brain endothelial cells [102]. The mechanism by which high glucose induces HIF-1α probably relates to RAGE activation [103] (Fig.…”

Section: Ascorbate Functions That May Decrease Pericyte Loss and Endomentioning

confidence: 99%

Ascorbic acid repletion: A possible therapy for diabetic macular edema?

May

2016

Free Radical Biology and Medicine

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Macular edema poses a significant risk for visual loss in persons with diabetic retinopathy. It occurs when plasma constituents and fluid leak out of damaged retinal microvasculature in the area of the macula, causing loss of central vision. Apoptotic loss of pericytes surrounding capillaries is perhaps the earliest feature of diabetic vascular damage in the macula, which is also associated with dysfunction of the endothelium and loss of the otherwise very tight endothelial permeability barrier. Increased oxidative stress is a key feature of damage to both cell types, mediated by excess superoxide from glucose-induced increases in mitochondrial metabolism, as well as by activation of the receptor for advanced glycation end products (RAGE). The latter in turn activates multiple pathways, some of which lead to increased oxidative stress, such as those involving NF-κB, NADPH oxidase, and endothelial nitric oxide synthase. Such cellular oxidative stress is associated with low cellular and plasma ascorbic acid levels in many subjects with diabetes in poor glycemic control. Whether repletion of low ascorbate in retinal endothelium and pericytes might help to prevent diabetic macular edema is unknown. However, cell culture studies show that the vitamin prevents high-glucose and RAGE-induced apoptosis in both cell types, that it preserves nitric oxide generated by endothelial cells, and that it tightens the leaky endothelial permeability barrier. Although these findings need to be confirmed in pre-clinical animal studies, it is worth considering clinical trials to determine whether adequate ascorbate repletion is possible and whether it might help to delay or even reverse early diabetic macular edema.

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Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1

Cited by 148 publications

References 41 publications

HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells

HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells

Caffeic acid phenethyl amide ameliorates ischemia/reperfusion injury and cardiac dysfunction in streptozotocin-induced diabetic rats

Ascorbic acid repletion: A possible therapy for diabetic macular edema?

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