Metformin reduces vascular endothelial dysfunction caused by an acute glucose load in patients with hypertension

Tingxing, Zhang; Xu, Junxia; Peng, Feng; Chai, Dongqi; Lin, Jinxiu

doi:10.3109/08037051.2012.732761

Cited by 11 publications

(7 citation statements)

References 32 publications

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“…Preclinical in vivo studies and clinical data suggest that metformin possesses pleiotropic effects that protect the endothelium (Mather et al, 2001;Zhang et al, 2013;Arunachalam et al, 2014;Kinaan et al, 2015). However, the effect of metformin on miR-34a and its impact on endothelial function have not previously been studied.…”

Section: Discussionmentioning

confidence: 99%

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin

Arunachalam

Lakshmanan

Samuel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Impaired angiogenesis is a prominent risk factor that contributes to the development of diabetes-associated cardiovascular disease. MicroRNAs (miRNAs), small noncoding RNAs, are implicated as important regulators of vascular function, including endothelial cell differentiation, proliferation, and angiogenesis. In silico analysis and in vitro studies indicate that silent information regulator 1 (SIRT1) is a potential target for endothelial cell-specific miRNAs. In this study, we investigated the molecular crosstalk between miR-34a, the protein product of SIRT1 (sirtuin1), and the antidiabetic drug, metformin, in hyperglycemia-mediated impaired angiogenesis in mouse microvascular endothelial cells (MMECs). MMECs were cultured, transfected with either a miR-34a inhibitor or mimic in normal glucose (11 mM) or high glucose (HG, 40 mM) in the presence or absence of metformin. The expression of miR-34a, sirtuin1, and their signaling targets was evaluated. miR-34a expression is upregulated in a hyperglycemic milieu and parallels changes in the expression of sirtuin1, post-translational modification of endothelial nitric oxide synthase (phospho/acetylation), as well as an impairment in angiogenesis. The presence of metformin, or the inhibition of miR-34a using an anti-miR-34a inhibitor, increases the expression of sirtuin1 and attenuates the impairment in angiogenesis in HG-exposed MMECs. In contrast, overexpression of a miR-34a mimic prevents metformin-mediated protection. These data indicate that miR-34a, via the regulation of sirtuin1 expression, has an anti-angiogenic action in MMECs, which can be modulated by metformin. In summary, miR-34a represents both a target whereby metformin mediates its vasculoprotective actions and also a potential therapeutic target for the prevention/treatment of diabetic vascular disease.

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Section: Discussionmentioning

confidence: 99%

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin

Arunachalam

Lakshmanan

Samuel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…(), it is of particular interest that Zhang et al . () have reported that a single 500 mg dose of metformin prevents the reduction of brachial artery FMD following an oral glucose load in patients with primary hypertension. Collectively, these data from a combination of clinical and in vitro studies strongly suggest that metformin does have a direct endothelial protective action that is most likely, at least in part, mediated via eNOS and, possibly, involving an antioxidant action and can have a rapid onset of action as reflected by the data presented by Zhang et al .…”

Section: Cellular Mode Of Action: Role Of Amp Kinase (Ampk)mentioning

confidence: 99%

Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium

Triggle

Ding

2016

Acta Physiol

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Metformin, a synthetic dimethyl biguanide, has been in clinical use for over 55 years, and today is considered the first-choice drug for the treatment of type 2 diabetes used by an estimated 125 million people worldwide. Metformin is orally effective, not metabolized, excreted unchanged by the kidney, relatively free of side effects and well tolerated by the majority of patients. Of importance is that the United Kingdom Prospective Diabetes Study 20-year study of type 2 diabetics, completed in 1998, compared patients treated with insulin, sulfonylureas and metformin and concluded that metformin provided vascular protective actions. Cardiovascular disease is the primary basis for the high morbidity and mortality that is associated with diabetes and that metformin proved to be protective resulted in a dramatic increase in its use. The vascular protective actions of metformin are thought to be secondary to the antihyperglycaemic effects of metformin that are mediated via activation of AMP kinase and subsequent inhibition of hepatic gluconeogenesis, fatty acid oxidation as well as an insulin sensitizing action in striated muscle and adipose tissue. As reflected by a number of clinical studies, patients treated with metformin also have improvement in endothelial function as measured by the use of plethysmography and measurement of flow-mediated vasodilatation. These data as well as data from animal studies are supportive that metformin has a direct protective action on the vascular endothelium. In this review article, we discuss the pharmacology of metformin and critique the literature as to its cellular sites and mechanism(s) of action.

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“…Fourteen of these articles reported vascular data for multiple subgroups of a given or diverse health status; thus, they were assessed as individual studies. 22,[25][26][27][28]31,37,38,45,52,[56][57][58][59] The main characteristics and clinical data for these studies are shown in Tables 1 and 2, respectively. Three potentially relevant studies were not available for full text reading and thus could not be included.…”

Section: Study Selection and Characteristicsmentioning

confidence: 99%

Acute Hyperglycemia Impairs Vascular Function in Healthy and Cardiometabolic Diseased Subjects

Loader

Montero

Lorenzen

et al. 2015

ATVB

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Objectives-Controversy exists over the effect of acute hyperglycemia on vascular function. In this systematic review, we compared the effect of acute hyperglycemia on endothelial and vascular smooth muscle functions across healthy and cardiometabolic diseased subjects. Approach and Results-A systematic search of MEDLINE, EMBASE, and Web of Science from inception until July 2014 identified articles evaluating endothelial or vascular smooth muscle function during acute hyperglycemia and normoglycemia. Meta-analyses compared the standardized mean difference (SMD) in endothelial and vascular smooth muscle functions between acute hyperglycemia and normoglycemia. Subgroup analyses and metaregression identified sources of heterogeneity. Thirty-nine articles (525 healthy and 540 cardiometabolic subjects) were analyzed. Endothelial function was decreased (39 studies; n=1065; SMD, −1.25; 95% confidence interval, −1.52 to −0.98; P<0.01), whereas vascular smooth muscle function was preserved (6 studies; n=144; SMD, −0.07; 95% confidence interval, −0.30 to 0.16; P=0.55) during acute hyperglycemia compared with normoglycemia. Significant heterogeneity was detected among endothelial function studies (P<0.01). A subgroup analysis revealed that endothelial function was decreased in the macrocirculation (30 studies; n=884; SMD, −1.40; 95% confidence interval, −1.68 to −1.12; P<0.01) but not in the microcirculation (9 studies; n=181; SMD, −0.63; 95% confidence interval, −1.36 to 0.11; P=0.09). Similar results were observed according to health status. Macrovascular endothelial function was inversely associated with age, blood pressure, and low-density lipoprotein cholesterol and was positively associated with the postocclusion interval of vascular assessment. Conclusions-To our knowledge, this is the first systematic review and meta-analysis of its kind. In healthy and diseased subjects, we found evidence for macrovascular but not microvascular endothelial dysfunction during acute hyperglycemia. Loader et al Acute Hyperglycemia Impairs Vascular Function 2061in vitro studies suggest that acute hyperglycemia may also impair VSM function by disrupting VSM cell apoptosis, causing subsequent VSM cell proliferation and desensitization to NO. [19][20][21] However, whether endothelial and VSM functions are transiently impaired during acute hyperglycemia in humans is unclear because of discrepant results. Given this, we conducted a systematic review and meta-analysis of available studies comparing endothelial function alone or in combination with VSM function during acute hyperglycemia in healthy and cardiometabolic diseased individuals. To our knowledge, this represents the first systematic review and meta-analysis to assess the effect of acute hyperglycemia on vascular function. Materials and MethodsMaterials and methods are available in the online-only Data Supplement. Results Study Selection and CharacteristicsA flowchart of study selection is shown in Figure 1. The systematic search resulted in the inclusion of 39 from 394 potential a...

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Metformin reduces vascular endothelial dysfunction caused by an acute glucose load in patients with hypertension

Abstract: Metformin can prevent transient endothelial dysfunction caused by acute glucose load in patients with PH.

Cited by 11 publications

References 32 publications

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin

Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium

Acute Hyperglycemia Impairs Vascular Function in Healthy and Cardiometabolic Diseased Subjects

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