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Molecular Medicine

, Volume 21, Issue 1, pp 1–14 | Cite as

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

  • Ciro Coletta
  • Katalin Módis
  • Bartosz Szczesny
  • Attila Brunyánszki
  • Gábor Oláh
  • Ester C. S. Rios
  • Kazunori Yanagi
  • Akbar Ahmad
  • Andreas Papapetropoulos
  • Csaba Szabo
Research Article

Abstract

Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 µmol/L to 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia.

Notes

Acknowledgments

This work was supported by the American Diabetes Association (7-12-BS-184) and the National Institutes of Health (R01GM107846) to C Szabo. C Coletta was supported by a fellowship by the American Heart Association. K Módis was supported by the James W. McLaughlin Fellowship Fund of the University of Texas. The editorial assistance of Ms. Li Li Szabo is appreciated.

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Authors and Affiliations

  • Ciro Coletta
    • 1
  • Katalin Módis
    • 1
  • Bartosz Szczesny
    • 1
  • Attila Brunyánszki
    • 1
  • Gábor Oláh
    • 1
  • Ester C. S. Rios
    • 1
  • Kazunori Yanagi
    • 1
  • Akbar Ahmad
    • 1
  • Andreas Papapetropoulos
    • 2
  • Csaba Szabo
    • 1
  1. 1.Department of AnesthesiologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Faculty of PharmacyUniversity of AthensAthensGreece

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