Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model

Takahashi, Noriko; Shibata, Rei; Ouchi, Noriyuki; Sugimoto, Masayuki; Murohara, Toyoaki; Komori, Kimihiro

doi:10.1016/j.jvs.2013.09.061

Cited by 43 publications

(37 citation statements)

References 41 publications

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“…#P<0.05, ###P<0.001 difference from ischemia group, $$$P<0.001 different from the Met+I/R group confirmed the metformin has no role on blood glucose level in ischemic or normal rats. There are many drugs which activate during its specified pathologic condition and it has no effect in normal condition (Takahashi et al 2015). According to the previous results and our findings, animal's appetite didn't change after ischemia so blood glucose level stayed on the given level.…”

Section: Discussionsupporting

confidence: 61%

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

et al. 2015

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Stroke is one of the main threats to the public health worldwide. Metformin, an anti-diabetic drug, is an activator of AMP-activated protein kinase (AMPK). Metformin plays an important role on improving behavior in neurodegenerative diseases through diverse pathways. In the current study we aimed to investigate the probable effects of metformin on anxiety and autophagy pathway in global cerebral ischemia. Rats were divided into seven groups; Sham, ischemia (I/R), metformin (met), compound c (CC), CC+ischemia, met+ischemia, met+CC+ischemia. Metformin was pretreated for 2 weeks and CC administrated half an hour before global cerebral ischemia. Blood glucose, body weight, sensorimotor scores, elevated plus maze and open field test were evaluated after ischemia. Autophagy related factors were measured by Western blot and immunofluorescent assay in hippocampus of rats. Based on our results, pretreatment of rats by metformin improved sensory motor signs, anxiolytic behavior and locomotion in ischemic rats. CC injection in I/R rats attenuated the therapeutic effects of metformin. Autophagy factors such as light chain 3B, Atg7, Atg5-12 and beclin-1 decreased in ischemic rats compared to the sham group (P < 0.001 in all proteins). Level of autophagic factors increased in metformin pretreated rats compared to global cerebral ischemia (P < 0.001 in all proteins). These data indicated that the beneficial role of metformin in behavior and autophagy flux mediates via AMPK. Our results recommended that metformin therapy could improve psychological disorders and movement disability following I/R and profound understanding of AMPK-dependent autophagy would enhance its development as a promising target for intracellular pathway.

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Section: Discussionsupporting

confidence: 61%

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

et al. 2015

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“…The glucose independent mechanism behind the metformin cardio-protective effect is of particular interest as this drug has some beneficial cardiac properties in non-diabetic animals [38]. When used in non-diabetic animals, metformin improved the outcome and revascularization following surgically induced myocardial infarction and hindlimb ischemia [38, 39]. Insulin dosage was reduced significantly, but it was not correlated with changes in cEPCs number or PACs adhesion.…”

Section: Discussionmentioning

confidence: 99%

Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study

Ahmed

Rider

Glanville

et al. 2016

Cardiovasc Diabetol

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BackgroundType 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.MethodsThis study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45dimCD34+VEGFR-2+ and CD45dimCD133−CD34+CD144+ respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill’s colonies).ResultsAt baseline TG had lower cEPCs, PACs, CFU-Hills’ colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill’s colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill’s colonies with cECs.ConclusionsMetformin has potential cardio-protective effect through improving cEPCs, CFU-Hill’s colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long term cardiovascular outcome studies in type 1 diabetes.Trial registration ISRCTN26092132Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0413-6) contains supplementary material, which is available to authorized users.

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“…Metformin and insulin administration are mainstream therapies in diabetes and have been shown to improve microvascular endothelial function directly and via improved glycemic control. Mechanisms of vascular protection by metformin include reducing endothelial cell senescence and apoptosis, attenuating hyperglycemia-induced oxidative stress[137], and promoting angiogenesis via AMP-k/eNOS pathways[138]. Similarly, insulin has a vasodilatory effect that is counteracted by chronic hyperglycemia[139] and resistance to insulin associates with microvascular endothelial damage driven by increase susceptibility to ischemia and loss of pro-survival effects.…”

Section: Potential Therapeutic Strategies: Protection Of Renal Microvmentioning

confidence: 99%

Role of the Renal Microcirculation in Progression of Chronic Kidney Injury in Obesity

Chade¹,

Hall²

2016

Am J Nephrol

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Background: Obesity is largely responsible for the growing incidence and prevalence of diabetes, cardiovascular and renal diseases. Current strategies to prevent and treat obesity and its consequences have been insufficient to reverse the ongoing trends. Lifestyle modification or pharmacological therapies often produce modest weight loss which is not sustained and recurrence of obesity is frequently observed, leading to progression of target organ damage in many obese subjects. Therefore, research efforts have focused not only on the factors that regulate energy balance, but also on understanding mechanisms of target organ injury in obesity. Summary and Key Message: Microvascular (MV) disease plays a pivotal role in progressive kidney injury from different etiologies such as hypertension, diabetes, and atherosclerosis, which are all important consequences of chronic obesity. The MV networks are anatomical units that are closely adapted to specific functions of nutrition and removal of waste in every organ. Damage of the small vessels in several tissues and organs has been reported in obesity and may increase cardio-renal risk. However, the mechanisms by which obesity and its attendant cardiovascular and metabolic consequences interact to cause renal MV injury and chronic kidney disease are still unclear, although substantial progress has been made in recent years. This review addresses potential mechanisms and consequences of obesity-induced renal MV injury as well as current treatments that may provide protection of the renal microcirculation and slow progressive kidney injury in obesity.

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Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model

Cited by 43 publications

References 41 publications

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study

Role of the Renal Microcirculation in Progression of Chronic Kidney Injury in Obesity

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