<p>Methylglyoxal (MG) is a reactive glucose metabolite and a known causative factor for hypertension and diabetes. Hydrogen sulfide (H<sub>2</sub>S), on the other hand, is a gasotransmitter with multifaceted physiological functions, including anti-oxidant and vasodilatory properties. The present study demonstrates that MG and H<sub>2</sub>S can interact with and modulate each other's functions. Upon <i>in vitro</i> incubations, we found that MG and H<sub>2</sub>S can directly interact to form three possible MG-H<sub>2</sub>S adducts. Furthermore, the endogenous production level of MG or H<sub>2</sub>S was significantly reduced in a concentration-dependent manner in rat vascular smooth muscle cells (A-10 cells) treated with NaHS, a H<sub>2</sub>S donor, or MG, respectively. Indeed, MG-treated A-10 cells exhibited a concentration-dependent down-regulation of the protein and activity level of cystathionine γ-lyase (CSE), the main H<sub>2</sub>S-generating enzyme in the vasculature. Moreover, H<sub>2</sub>S can induce the inhibition of MG-generated ROS production in a concentration-dependent manner in A-10 cells. In 6-22 week-old CSE knockout male mice (CSE<sup>-/-</sup>), mice with lower levels of vascular H<sub>2</sub>S, we observed a significant elevation in MG levels in both plasma and renal extracts. Renal triosephosphates were also significantly increased in the 6-22 week-old CSE<sup>-/-</sup> mice. To identify the source of the elevated renal MG levels, we found that the activity of fructose-1,6-bisphosphatase (FBPase), the rate-limiting enzyme in gluconeogenesis, was significantly down-regulated, along with lower levels of its product (fructose-6-phosphate) and higher levels of its substrate (fructose-1,6-bisphosphate) in the kidney of 6-22 week-old CSE<sup>-/-</sup> mice. We have also observed lower levels of the gluconeogenic regulator, peroxisome
proliferator-activated receptor-γ coactivator (PGC)-1α, and its down-stream targets, FBPase-1 and -2, phosphoenolpyruvate carboxykinase (PEPCK), and estrogen-related receptor (ERR)α mRNA expression levels in renal extracts from 6-22 week-old CSE<sup>-/-</sup> mice. Likewise, FBPase-1 and -2 mRNA levels were also significantly down-regulated in aorta tissues from 14-16 week-old CSE<sup>-/-</sup> mice. Administration of 30 and 50 µM NaHS induced a significant increase in FBPase-1 and PGC-1α in rat A-10 cells. We have also observed a significant up-regulation of PEPCK and ERRα mRNA expression levels in 50 µM NaHS-treated A-10 cells, further confirming the involvement of H<sub>2</sub>S in regulating the rate of gluconeogenesis and MG formation. Overall, this unique study demonstrates the existence of a negative correlation between MG and H<sub>2</sub>S in the vasculature. Further elucidation of this cross-talk phenomenon between MG and H<sub>2</sub>S could lead to more elaborate and effective therapeutic regimens to combat metabolic syndrome and its related health complications.</p>
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-05272011-203648 |
| Date | 24 June 2011 |
| Creators | Untereiner, Ashley Anne |
| Contributors | Dr. Lingyun Wu, Dr. Paul Lee, Dr. Steven Richardson, Dr. Kaushik Desai, Dr. Linda Hiebert, Dr. Thomas Fisher |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-05272011-203648/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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