Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARγ stimulation

Biscetti, Federico; Straface, Giuseppe; Arena, Vincenzo; Stigliano, Egidio; Pecorini, Giovanni; Rizzo, Paola; Angelis, Giulia De; Iuliano, Luigi; Ghirlanda, Giovanni; Flex, Andrea

doi:10.1186/1475-2840-8-49

Cited by 43 publications

(39 citation statements)

References 57 publications

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“…Low protein levels of VEGF were associated with capillary rarefaction in the present study as well as in kidneys of diabetic patients [28] and may originate from a deficient response of VEGF expression to stimulation via HIF [29]. Typically, TZDs stimulate VEGF expression and improve the angiogenic response to ischemia [24,30,31]. However, such activity was observed in our study.…”

Section: Discussioncontrasting

confidence: 53%

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Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Ashoff¹,

Qadri

Eggers

et al. 2012

J Vasc Res

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Background/Aims: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-γ transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. Methods: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. Results: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm² to 475/mm² in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3α and PPAR coactivator-1α (PGC-1α) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. Conclusion: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis.

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Section: Discussioncontrasting

confidence: 53%

“…Studies in the context of diabetes have focused on proangiogenic mechanisms that were induced by ischemia or simulated in vitro [24,25]. In contrast, the present study targeted the deterioration of microvascular structure imposed by diabetes alone.…”

Section: Discussionmentioning

confidence: 88%

Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Ashoff¹,

Qadri

Eggers

et al. 2012

J Vasc Res

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“…VEGF induction is dependent on quercetin-mediated hypoxia-inducible factor-1 (HIF-1) activation. Quercetin delays the appearance of HIF-1α protein by inhibiting HIF-prolyl hydroxylase (HPH), which is the key enzyme for HIF-1α hydroxylation and subsequent von Hippel Lindau-dependent HIF-1α degradation (12). Our data suggest that the clinical effect of quercetin may be partly attributed to the activation of the HIF-1-VEGF angiogenic pathway, through the inhibition of HPH, and that the chelating moieties of quercetin are required for the inhibition of HPH.…”

Section: Discussionmentioning

confidence: 82%

Effect of pioglitazone, quercetin, and hydroxy citric acid on vascular endothelial growth factor messenger RNA (VEGF mRNA) expression in experimentally induced nonalcoholic steatohepatitis (NASH)

Surapaneni¹,

Veeraraghavan²,

Jainu³

2015

Turk J Med Sci

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Background/aim: Vascular endothelial growth factor (VEGF) is associated with various ischemic and inflammatory diseases, and plays an important role in the development of liver fibrosis and hepatocarcinogenesis in nonalcoholic steatohepatitis (NASH). In this study, the comparative effect of pioglitazone, quercetin, and hydroxy citric acid on VEGF mRNA in experimentally induced NASH was investigated. Materials and methods:The experimental protocol consisted of five groups: control, NASH, NASH + pioglitazone, NASH + quercetin, and NASH + hydroxy citric acid. The VEGF mRNA expression was evaluated by reverse transcription polymerase chain reaction (RT-PCR) analysis for all experimental groups, and the levels of VEGF mRNA were quantitatively measured by densitometry.Results: A higher expression of VEGF mRNA was found in the hepatic cells of rats with experimentally induced NASH compared to the control group. A very mild increase in VEGF mRNA expression was observed in the rats treated with quercetin. In contrast, a mild increase in the expression of VEGF mRNA was observed in the rats treated with pioglitazone and hydroxy citric acid. Conclusion:Quercetin exhibited an effective inhibition of VEGF mRNA expression, while a lower inhibition of the VEGF mRNA level was observed in the hydroxy citric acid-and the pioglitazone-treated rats.

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“…El 15% de los diabéticos tipo 2 tratados con insulina desarrollará edema macular frente al 4% de los que sólo toman antidiabéticos orales. Generalmente la retención de líquidos por glitazonas es refractaria al tratamiento con diuréticos y se piensa que es secundaria a una alteración en el transporte iónico a nivel intestinal y renal, incrementando el volumen plasmático, la activación simpática y aumentando la permeablidad endotelial a través de un incremento plasmático del VEGF [1][2][3][4] .…”

Section: Discussionunclassified

Edema macular por tratamiento con rosiglitazona en diabetes mellitus

Asensio-Sánchez

Gómez-Ramírez

2010

Archivos de la Sociedad Española de Oftalmología

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Caso clínico: Mujer de 61 años diabética tipo 2 de 7 años de evolución en tratamiento con insulina. Se añade rosiglitazona (4 mg al día) para conseguir un control glucémico adecuado. Un mes después, la paciente presenta edema generalizado y pérdida de visión. El estudio fundoscópico mostró edema macular bilateral. En la exploración sistémica destacaban edemas periféricos. La rosiglitazona fue suspendida y la paciente fue tratada de forma conservadora, con resolución rápida de los edemas periféricos pero no de los maculares.Discusión: Este caso nos indica la importancia de identificar los efectos secundarios de las glitazonas. El tratamiento con glitazonas puede causar edema macular que podría permanecer aun después de su supresión. Case report: A 61-year-old woman with type 2 diabetes mellitus for 7 years for which she was prescribed insulin therapy. Rosiglitazone (4 mg once daily) was introduced with adequate blood glucose control. One month later, she presented with complaints of systemic oedema and loss of vision. Fundoscopy showed bilateral macular oedema. A systemic study demonstrated peripheral oedema. Rosiglitazone was stopped and she was managed conservatively with a rapid resolution of the oedemas and at fundus examination there was no decrease in the macular oedema. Macular oedema due to rosiglitazone treatment in diabetes mellitusDiscussion: This case reminds us of the importance of identifying potential toxicities of glitazone regimens. Glitazone use appears to be a cause of macular oedema, and stopping the drug may not resolve this oedema.

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Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARγ stimulation

Cited by 43 publications

References 57 publications

Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Effect of pioglitazone, quercetin, and hydroxy citric acid on vascular endothelial growth factor messenger RNA (VEGF mRNA) expression in experimentally induced nonalcoholic steatohepatitis (NASH)

Edema macular por tratamiento con rosiglitazona en diabetes mellitus

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