Hydrogen sulfide improves vessel formation of the ischemic adductor muscle and wound healing in diabetic db/db mice

Document Type: Original Article

Authors

Department of Pathophysiology, Wannan Medical College, Wuhu, China

Abstract

Objective(s): It has been demonstrated that hydrogen sulfide plays a vital role in physiological and pathological processes such as regulating inflammation, oxidative stress, and vessel relaxation. The aim of the study was to explore the effect of hydrogen sulfide on angiogenesis in the ischemic adductor muscles of type 2 diabetic db/db mice and ischemic diabetic wound healing.
Materials and Methods: The femoral arteries of diabetic db/db mice were isolated and ligated for preparation of ischemic hind limb model. Round incision was made on ischemic and non-ischemic limbs. The wounds were treated with sodium bisulfide (hydrogen sulfide donor). Real-time PCR and Western blotting were used to measure transcription of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet derived growth factor (PDGF), hypoxia inducible factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) and protein expression of VEGF, VEGF receptor (VEGFR) and PDGF, PDGF receptor (PDGFR), respectively. Angiogenesis and morphological changes in adductor muscles were observed.
Results: Hydrogen sulfide significantly increased transcription of VEGF, EGF, PDGF, HIF-1α, eNOS and protein expression of VEGF, PDGF, and phosphorylated VEGFR and PDGFR. Treatment with hydrogen sulfide significantly improved ischemic wound healing and formation of granulation tissue, and increased the number of small vessels in the ischemic adductor muscles.
Conclusion: Our data suggested that hydrogen sulfide attenuated injury of ischemic adductor muscle, and promoted the ischemic diabetic wound healing via modulating angiogenesis in type 2 diabetic db/db mice.

Keywords

Main Subjects


1. Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med 2007; 147:149-155.
2. Dash SN, Dash NR, Guru B, Mohapatra PC. Towards reaching the target: clinical application of mesenchymal stem cells for diabetic foot ulcers. Rejuvenation Res 2014; 17:40-53.
3. Srikanth S, Deedwania P. Primary and secondary prevention strategy for cardiovascular disease in diabetes mellitus. Cardiol Clin 2011; 29:47-70.
4. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986.
5. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005; 366:1736-1743.
6. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther 2008; 88:1254-1264.
7. Shyu KG, Manor O, Magner M, Yancopoulos GD, Isner JM. Direct intramuscular injection of plasmid DNA encoding angiopoietin-1 but not angiopoietin-2 augments revascularization in the rabbit ischemic hindlimb. Circulation 1998; 98:2081-2087.
8. Li H, Fu X, Zhang L, Huang Q, Wu Z, Sun T. Research of PDGF-BB gel on the wound healing of diabetic rats and its pharmacodynamics. J Surg Res 2008; 145:41-48.
9. Lizotte F, Pare M, Denhez B, Leitges M, Guay A, Geraldes P. PKCdelta impaired vessel formation and angiogenic factor expression in diabetic ischemic limbs. Diabetes 2013; 62:2948-2957.
10. Robson MC, Phillips LG, Thomason A, Robson LE, Pierce GF. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992; 339:23-25.
11. Li X, Gan K, Song G, Wang C. VEGF gene transfected umbilical cord mesenchymal stem cells transplantation improve the lower limb vascular lesions of diabetic rats. J Diabetes Complications 2015; 29:872-881.
12. Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, et al. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 2002; 105:373-379.
13. Frank S, Hubner G, Breier G, Longaker MT, Greenhalgh DG, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem 1995; 270:12607-12613.
14. Reiffenstein RJ, Hulbert WC, Roth SH. Toxicology of hydrogen sulfide. Annu Rev Pharmacol Toxicol 1992; 32:109-134.
15. Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 1996; 16:1066-1071.
16. Vacek TP, Gillespie W, Tyagi N, Vacek JC, Tyagi SC. Hydrogen sulfide protects against vascular remodeling from endothelial damage. Amino Acids 2010; 39:1161-1169.
17. Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J 2006; 20:2118-2120.
18. Teague B, Asiedu S, Moore PK. The smooth muscle relaxant effect of hydrogen sulphide in vitro: evidence for a physiological role to control intestinal contractility. Br J Pharmacol 2002; 137:139-145.
19. Qu K, Lee SW, Bian JS, Low CM, Wong PT. Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 2008; 52:155-165.
20. Shen Y, Shen Z, Miao L, Xin X, Lin S, Zhu Y, et al. miRNA-30 family inhibition protects against cardiac ischemic injury by regulating cystathionine-gamma-lyase expression. Antioxid Redox Signal 2015; 22:224-240.
21. Qipshidze N, Metreveli N, Mishra PK, Lominadze D, Tyagi SC. Hydrogen sulfide mitigates cardiac remodeling during myocardial infarction via improvement of angiogenesis. Int J Biol Sci 2012; 8:430-441.
22. Luan HF, Zhao ZB, Zhao QH, Zhu P, Xiu MY, Ji Y. Hydrogen sulfide postconditioning protects isolated rat hearts against ischemia and reperfusion injury mediated by the JAK2/STAT3 survival pathway. Braz J Med Biol Res 2012; 45:898-905.
23. Huang J, Wang D, Zheng J, Huang X, Jin H. Hydrogen sulfide attenuates cardiac hypertrophy and fibrosis induced by abdominal aortic coarctation in rats. Mol Med Rep 2012; 5:923-928.
24. Majumder A, Singh M, George AK, Behera J, Tyagi N, Tyagi SC. Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-beta-synthase mutant mice via PPAR-gamma/VEGF axis. Physiol Rep 2018; 6:e13858.
25. Wang G, Li W, Chen Q, Jiang Y, Lu X, Zhao X. Hydrogen sulfide accelerates wound healing in diabetic rats. Int J Clin Exp Pathol 2015; 8:5097-5104.
26. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275:964-967.
27. Tepper OM, Capla JM, Galiano RD, Ceradini DJ, Callaghan MJ, Kleinman ME, et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood 2005; 105:1068-1077.
28. Marrotte EJ, Chen DD, Hakim JS, Chen AF. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 2010; 120:4207-4219.
29. Li L, Whiteman M, Guan YY, Neo KL, Cheng Y, Lee SW, et al. Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 2008; 117:2351-2360.
30. Szabo C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 2007; 6:917-935.
31. Coletta C, Papapetropoulos A, Erdelyi K, Olah G, Modis K, Panopoulos P, et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc Natl Acad Sci U S A 2012; 109:9161-9166.
32. Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, Zhu YC. The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antioxid Redox Signal 2010; 12:1065-1077.
33. Wang P, Xie ZH, Guo YJ, Zhao CP, Jiang H, Song Y, et al. VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer’s disease. Biochem Biophys Res Commun 2011; 411:620-626.
34. Hou C, Shen L, Huang Q, Mi J, Wu Y, Yang M, et al. The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer. Biomaterials 2013; 34:112-120.
35. Roskoski R, Jr. VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun 2008; 375:287-291.
36. Boor P, van Roeyen CR, Kunter U, Villa L, Bucher E, Hohenstein B, et al. PDGF-C mediates glomerular capillary repair. Am J Pathol 2010; 177:58-69.
37. Zhao Y, Zhang S, Zeng D, Xia L, Lamichhane A, Jiang X, et al. rhPDGF-BB promotes proliferation and osteogenic differentiation of bone marrow stromal cells from streptozotocin-induced diabetic rats through ERK pathway. Biomed Res Int 2014; 2014:637415.
38. Xie Z, Paras CB, Weng H, Punnakitikashem P, Su LC, Vu K, et al. Dual growth factor releasing multi-functional nanofibers for wound healing. Acta Biomater 2013; 9:9351-9359.
39. Lee CH, Liu KS, Chang SH, Chen WJ, Hung KC, Liu SJ, et al. Promoting diabetic wound therapy using biodegradable rhpdgf-loaded nanofibrous membranes: CONSORT-Compliant Article. Medicine (Baltimore) 2015; 94:e1873.
40. Sarkar K, Fox-Talbot K, Steenbergen C, Bosch-Marce M, Semenza GL. Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci U S A 2009; 106:18769-18774.
41. Roguin A, Nitecki S, Rubinstein I, Nevo E, Avivi A, Levy NS, et al. Vascular endothelial growth factor (VEGF) fails to improve blood flow and to promote collateralization in a diabetic mouse ischemic hindlimb model. Cardiovasc Diabetol 2003; 2:18.
42. Khan TA, Sellke FW, Laham RJ. Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther 2003; 10:285-291.
43. Tanii M, Yonemitsu Y, Fujii T, Shikada Y, Kohno R, Onimaru M, et al. Diabetic microangiopathy in ischemic limb is a disease of disturbance of the platelet-derived growth factor-BB/protein kinase C axis but not of impaired expression of angiogenic factors. Circ Res 2006; 98:55-62.
44. Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, et al. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 2009; 15:1298-1306.