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A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.

ABSTRACT: Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin-methylglyoxal scavenging reaction, (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl) guanidine (IMZ), was recently characterized and identified in the urine of type-2 diabetic patients. Here, we report the pro-angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro-angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia-inducible factor-1 alpha (HIF-1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post-ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro-angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro-angiogenic agents for the treatment of PAD.

SUBMITTER: Nguyen H

PROVIDER: S-EPMC8237315 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.

Nguyen Huong H Koh Jia Yi JY Li Hainan H Islas-Robles Argel A Meda Venkata Sai Pranathi SP Wang Jie-Mei JM Monks Terrence J TJ

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20210701 7

Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin-methylglyoxal scavenging reaction, (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl) guanidine (IMZ), was recently characterized and identified in the urine of type-2 d ...[more]

PMID: 34105824

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Project description:UnlabelledPioglitazone was associated with increased hazard for surgical or percutaneous lower extremity revascularization in patients with diabetes in a large clinical trial, but this clinical finding has not been adequately explored in animal models. We hypothesized that pioglitazone would decrease hypoxia-inducible factor 1α (HIF-1α)-dependent angiogenesis in rat ischemic hindlimb models by altering mitochondrial-derived signals supporting HIF-1α activation. We tested oral pioglitazone (10 mg/kg/day) versus placebo in two cohorts of rats with hindlimb ischemia (normal Sprague-Dawley rats and insulin-resistant JCR:La-cp rats), and evaluated direct and paracrine effects of pioglitazone on angiogenesis in vitro using human skeletal muscle and endothelial cells. Pioglitazone treatment was associated with reductions in limb perfusion at 2 weeks measured by contrast-enhanced ultrasound and Tc(99m)-Sestamibi SPECT-CT. Ischemic muscle capillary density was also reduced by pioglitazone. HIF-1α and vascular endothelial growth factor (VEGF) expression in ischemic muscle were also reduced by pioglitazone. In vitro, pioglitazone's effects on both skeletal muscle cells and microvascular endothelial cells were associated with a decrease in autocrine and paracrine angiogenesis measured by matrigel assay, decreased HIF-1α expression and activation, as well as increases in both mitochondrial reactive oxygen species and α-ketoglutarate, both mitochondria-derived signals which promote HIF-1α degradation. We conclude that pioglitazone is associated with decreased ischemic limb perfusion and capillary density in relevant rat models of hindlimb ischemia, and these effects are mediated by mitochondria-dependent reductions in HIF-1α-dependent angiogenesis.Key messagesPioglitazone inhibits angiogenesis in rats with and without insulin resistance. Pioglitazone inhibits HIF-1α by inhibiting mitochondrial stabilization of HIF-1. Pioglitazone inhibits both autocrine and paracrine angiogenesis. Inhibition of angiogenesis may explain unexpected results of a pioglitazone human clinical trial.

Dataset Information

A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.

Publications

A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.

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