Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells

Eriksson, Linnéa; Erdogdu, Özlem; Nyström, Thomas; Zhang, Qimin; Sjöholm, Åke

doi:10.1186/1475-2840-11-27

Cited by 18 publications

(19 citation statements)

References 45 publications

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“…Nevertheless, vasorelaxation was significantly restored in rats that received treatment with metformin. We and others have demonstrated that impairment of endothelium-dependent vasorelaxation may be mediated by MG while metformin treatment significantly improves endothelial function and vasorelaxation [8,18,35-37]. These findings suggest that the improvement of endothelial function and vessel reactivity may be attributed to the effects of metformin on reduction of MG levels and improvement of insulin sensitivity [38].…”

Section: Discussionmentioning

confidence: 81%

The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats

Lü

Meng

et al. 2013

Cardiovasc Diabetol

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BackgroundInsulin resistance is strongly associated with the development of type 2 diabetes and cardiovascular disease. However, the underlying mechanisms linking insulin resistance and the development of atherosclerosis have not been fully elucidated. Moreover, the protective effect of antihyperglycemic agent, metformin, is not fully understood. This study investigated the protective effects and underlying mechanisms of metformin in balloon-injury induced stenosis in insulin resistant rats.MethodsAfter 4 weeks high fructose diet, rats received balloon catheter injury on carotid arteries and were sacrificed at 1 and 4 weeks post injury. Biochemical, histological, and molecular changes were investigated.ResultsPlasma levels of glucose, insulin, total cholesterol, triglyceride, free fatty acids, and methylglyoxal were highly increased in fructose-induced insulin resistant rats and treatment with metformin significantly improved this metabolic profile. The neointimal formation of the carotid arteries was enhanced, and treatment with metformin markedly attenuated neointimal hyperplasia. A significant reduction in BrdU-positive cells in the neointima was observed in the metformin-treated group (P < 0.01). Insulin signaling pathways were inhibited in insulin resistant rats while treatment with metformin enhanced the expression of insulin signaling pathways. Increased expression of JNK and NFKB was suppressed following metformin treatment. Vasoreactivity was impaired while treatment with metformin attenuated phenylephrine-induced vasoconstriction and enhanced methacholine-induced vasorelaxation of the balloon injured carotid arteries in insulin resistant rats.ConclusionThe balloon-injury induced neointimal formation of the carotid arteries is enhanced by insulin resistance. Treatment with metformin significantly attenuates neointimal hyperplasia through inhibition of smooth muscle cell proliferation, migration, and inflammation as well as by improvement of the insulin signaling pathway.

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Section: Discussionmentioning

confidence: 81%

The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats

Lü

Meng

et al. 2013

Cardiovasc Diabetol

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“…In nondiabetic experimental animal models, metformin prevents endotoxin-induced liver injury after partial hepatectomy (Bergheim et al 2006) and protects against carbon tetrachloride-induced hepatotoxicity in mice (Poon et al 2003). Furthermore, metformin has been shown to protect endothelial cells and neuronal cells in several in vitro toxicity models, possibly related to protection against oxidative stress (El-Mir et al 2008;Eriksson et al 2012;Bhatt et al 2013). However, the mechanism(s) involved in these protective effects of metformin has not been elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

Metformin protects primary rat hepatocytes against oxidative stress‐induced apoptosis

Rosa

Vrenken

Buist‐Homan

et al. 2015

Pharmacology Res & Perspec

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The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiology of diabetes complications. Metformin has been shown to be hepatoprotective in the insulin-resistant and leptin-deficient ob/ob mouse model of NAFLD. However, the mechanism involved in the protective effects of metformin has not been elucidated yet. Therefore, we investigated the protective effect of metformin against oxidative stress-induced apoptosis. Primary rat hepatocytes were exposed to the oxidative stress-generating compound menadione in the presence and absence of metformin. Apoptosis was determined by measuring caspase activity and poly(ADP-ribose) polymerase (PARP)-cleavage, and necrosis was measured by Sytox Green nuclear staining. We demonstrate that (1) Metformin inhibits menadione-induced caspase-9,-6,-3 activation and PARP-cleavage in a concentration-dependent manner. (2) Metformin increases menadione-induced heme oxygenase-1 (HO-1) expression and inhibits c-Jun N-terminal kinase (JNK)-phosphorylation. (3) Metformin does not induce necrosis in primary hepatocytes. Metformin protects hepatocytes against oxidative stress-induced caspase activation, PARP-cleavage and apoptosis. The anti-apoptotic effect of metformin is in part dependent on HO-1 and bcl-xl induction and inhibition of JNK activation and independent of insulin signaling. Our results elucidate novel protective mechanisms of metformin and indicate that metformin could be investigated as a novel therapeutic agent for the treatment of oxidative stress-related liver diseases.

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“…Cells were fasted overnight in serum-free 1640 medium followed by incubation for 24 hours with high glucose (33 mM) in the absence or presence of nifedipine (Sigma, N7634; 1μm), irbesartan (Sigma, 1347700; 5μm), metformin (Sigma, D150959; 10μM), glibenclamide (Sigma, G0639; 0.2 μM) and glimepiride (Sigma, G2295; 1 μM). The glucose level (33 mM) used in the present work was determined according to previous studies [8,11,13]. The concentrations of the antidiabetic and antihypertensive agents were determined according to their plasma concentrations [14][15][16][17].…”

Section: Huvecs Culture and Treatmentmentioning

confidence: 99%

“…Abnormalities in endothelial cell morphology and function are recognized as features of diabetes [8,9], while endothelial dysfunction is also characteristic of hypertension [10]. Therefore, endothelial function reservation has been more than vital in cardiovascular disease treatment [11,12].…”

Section: Introductionmentioning

confidence: 99%

Combination Therapy of Nifedipine and Sulphonylureas Exhibits a Mutual Antagonistic Effect on the Endothelial Cell Dysfunction Induced by Hyperglycemia Linked to Vascular Disease

Wang¹,

Yu²,

Yang³

et al. 2016

Cell Physiol Biochem

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Background/Aims: By inducing severe endothelial impairment, hypertension and diabetes are two leading causes of morbidity and mortality. Hypertensive patients with concomitant diabetes must take both antihypertensive and hypoglycaemic medications, for which there is a lack of experimental and clinical guidelines. This study aimed to examine the interaction between these two types of medication on the endothelial cell function. Methods: The effect of antihypertensive (nifedipine and irbesartan) and anti-diabetic (metformin and glibenclamide/glimepiride) drugs on human umbilical vein cells (HUVECs) function was examined using a modified Boyden chamber assay. The intracellular NO and O₂^- levels of HUVECs were detected through flow cytometry. Results: Our findings showed that nifedipine/sulphonylurea monotherapy significantly attenuated high glucose-induced (33 mM) HUVECs migration incapacity, while combination therapy of nifedipine and glibenclamide/glimepiride showed no protective effect. Both nifedipine/metformin monotherapy and combined therapy significantly mitigated the migration incapacity induced by high glucose in HUVECs. Combined with either metformin or sulphonylureas, irbesartan therapy was able to attenuate the high glucose-induced migration incapacity of HUVECs. Nifedipine monotherapy decreased the O₂^- levels and increased the NO levels in in vitro-cultured HUVECs treated with high glucose. However, the combination therapy of nifedipine and glibenclamide increased the O₂^- levels and decreased the NO levels compared to the nifedipine monotherapeutic group. Conclusion: The nifedipine and glibenclamide/glimepiride combination exerted a mutual antagonistic effect on the protection from high glucose-induced impairment in endothelial cells, which might be partially attributed to the increased O₂^- level and decreased NO level. These results imply that calcium channel blockers + sulphonylurea combination therapy warrants further attention in patients suffering from both hypertension and diabetes.

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Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells

Cited by 18 publications

References 45 publications

The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats

The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats

Metformin protects primary rat hepatocytes against oxidative stress‐induced apoptosis

Combination Therapy of Nifedipine and Sulphonylureas Exhibits a Mutual Antagonistic Effect on the Endothelial Cell Dysfunction Induced by Hyperglycemia Linked to Vascular Disease

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