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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
- Source :
- Molecular Medicine. 21:1-14
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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 μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 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.
- Subjects :
- Male
medicine.medical_specialty
Endothelium
Angiogenesis
Vasodilator Agents
Neovascularization, Physiologic
Cellular homeostasis
Biology
Cell Line
Neovascularization
Mice
chemistry.chemical_compound
Oxygen Consumption
Dihydrolipoic acid
In vivo
Internal medicine
Cyclic GMP-Dependent Protein Kinases
Diabetes Mellitus
Genetics
medicine
Animals
Cysteine
Hydrogen Sulfide
Molecular Biology
Genetics (clinical)
Thioctic Acid
Endothelial Cells
Articles
equipment and supplies
Mitochondria
Rats
Endothelial stem cell
Disease Models, Animal
Lipoic acid
Endocrinology
medicine.anatomical_structure
chemistry
Hyperglycemia
Sulfurtransferases
Molecular Medicine
Endothelium, Vascular
medicine.symptom
Energy Metabolism
Proto-Oncogene Proteins c-akt
Metabolic Networks and Pathways
Subjects
Details
- ISSN :
- 15283658 and 10761551
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Molecular Medicine
- Accession number :
- edsair.doi.dedup.....0abdb11bdbcdcd3cfcfcf76bb9241383