Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2015 Molecular Medicine. All rights received.
Συγγραφείς:
Coletta, C.
Módis, K.
Szczesny, B.
Brunyánszki, A.
Oláh, G.
Rios, E.C.S.
Yanagi, K.
Ahmad, A.
Papapetropoulos, A.
Szabo, C.
Περιοδικό:
Current Molecular Medicine
Εκδότης:
Uninversity of Michigan
Λέξεις-κλειδιά:
3 mercaptopyruvic acid; 3 mercaptopyruvic acid sulfurtransferase; cyclic GMP dependent protein kinase; cytochrome c oxidase; dihydrolipoate; glucose; hydrogen sulfide; protein kinase B; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone); succinate dehydrogenase (ubiquinone); sulfurtransferase; thioctic acid; ubiquinol cytochrome c reductase; unclassified drug; 3-mercaptopyruvate sulphurtransferase; 3-mercaptopyruvic acid; cyclic GMP dependent protein kinase; cysteine; hydrogen sulfide; protein kinase B; sulfurtransferase; thioctic acid; vasodilator agent, angiogenesis; animal cell; animal experiment; animal model; animal tissue; antioxidant activity; arterial pressure; Article; bioenergy; blood level; blood vessel tone; capillary endothelial cell; cell free system; concentration response; diabetic angiopathy; disorders of mitochondrial functions; endothelial dysfunction; endothelium cell; enzyme activation; enzyme activity; hyperglycemia; in vitro study; in vivo study; male; mitochondrial dynamics; mouse; nonhuman; pathogenesis; priority journal; rat; skin blood flow; skin capillary; streptozotocin-induced diabetes mellitus; vasodilatation; wound healing; wound healing impairment; analogs and derivatives; animal; blood; cell line; diabetes mellitus; disease model; drug effects; energy metabolism; genetics; hyperglycemia; metabolism; mitochondrion; oxygen consumption; physiology; vascular endothelium, Animals; Cell Line; Cyclic GMP-Dependent Protein Kinases; Cysteine; Diabetes Mellitus; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Energy Metabolism; Hydrogen Sulfide; Hyperglycemia; Male; Metabolic Networks and Pathways; Mice; Mitochondria; Neovascularization, Physiologic; Oxygen Consumption; Proto-Oncogene Proteins c-akt; Rats; Sulfurtransferases; Thioctic Acid; Vasodilator Agents
DOI:
10.2119/molmed.2015.00035
