{"id":{"repo_id":"sask","oai_identifier":"oai:harvest.usask.ca:10388/etd-05272011-203648"},"canonical_url":"https://search.dev.ndltd.org/etd/sask/oai:harvest.usask.ca:10388/etd-05272011-203648","repository":{"repo_id":"sask","name":"University of Saskatchewan","base_url":"https://harvest.usask.ca/server/oai/request"},"display":{"title":"Enhanced methylglyoxal formation in cystathionine γ-lyase knockout mice","abstract":"Methylglyoxal (MG) is a reactive glucose metabolite and a known causative factor for hypertension and diabetes. Hydrogen sulfide (H₂S), on the other hand, is a gasotransmitter with multifaceted physiological functions, including anti-oxidant and vasodilatory properties. The present study demonstrates that MG and H₂S can interact with and modulate each other's functions. Upon in vitro incubations, we found that MG and H₂S can directly interact to form three possible MG-H₂S adducts. Furthermore, the endogenous production level of MG or H₂S was significantly reduced in a concentration-dependent manner in rat vascular smooth muscle cells (A-10 cells) treated with NaHS, a H₂S 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 H₂S-generating enzyme in the vasculature. Moreover, H₂S 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⁻/⁻), mice with lower levels of vascular H₂S, 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⁻/⁻ 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⁻/⁻ 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⁻/⁻ mice. Likewise, FBPase-1 and -2 mRNA levels were also significantly down-regulated in aorta tissues from 14-16 week-old CSE⁻/⁻ 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 H₂S in regulating the rate of gluconeogenesis and MG formation. Overall, this unique study demonstrates the existence of a negative correlation between MG and H₂S in the vasculature. Further elucidation of this cross-talk phenomenon between MG and H₂S could lead to more elaborate and effective therapeutic regimens to combat metabolic syndrome and its related health complications.","abstract_html":"Methylglyoxal (MG) is a reactive glucose metabolite and a known causative factor for hypertension and diabetes. Hydrogen sulfide (H₂S), on the other hand, is a gasotransmitter with multifaceted physiological functions, including anti-oxidant and vasodilatory properties. The present study demonstrates that MG and H₂S can interact with and modulate each other's functions. Upon in vitro incubations, we found that MG and H₂S can directly interact to form three possible MG-H₂S adducts. Furthermore, the endogenous production level of MG or H₂S was significantly reduced in a concentration-dependent manner in rat vascular smooth muscle cells (A-10 cells) treated with NaHS, a H₂S 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 H₂S-generating enzyme in the vasculature. Moreover, H₂S 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⁻/⁻), mice with lower levels of vascular H₂S, 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⁻/⁻ 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⁻/⁻ 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⁻/⁻ mice. Likewise, FBPase-1 and -2 mRNA levels were also significantly down-regulated in aorta tissues from 14-16 week-old CSE⁻/⁻ 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 H₂S in regulating the rate of gluconeogenesis and MG formation. Overall, this unique study demonstrates the existence of a negative correlation between MG and H₂S in the vasculature. Further elucidation of this cross-talk phenomenon between MG and H₂S could lead to more elaborate and effective therapeutic regimens to combat metabolic syndrome and its related health complications.","abstract_has_math":false,"creators":["Untereiner, Ashley Anne"],"institution":"University of Saskatchewan","degree_name":"Master of Science (M.Sc.)","degree_level":"Masters","degree_discipline":"Pharmacology","degree_department":null,"school":null,"contributors":[],"advisors":["Dr. Lingyun Wu"],"committee_chairs":[],"committee_members":["Dr. Paul Lee","Dr. Steven Richardson","Dr. Kaushik Desai","Dr. Linda Hiebert","Dr. Thomas Fisher"],"year":2011,"date_issued":"2011-05-01","date_published":"2011-05-01","updated_at":"2026-07-24T04:26:49Z","subjects":["Hydrogen sulfide","Fructose-1 6-bisphosphatase","Vascular smooth muscle cells","Peroxisome proliferator-activated receptor-g","Methylglyoxal","Reactive oxygen species"],"languages":["en_US"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10388/etd-05272011-203648","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Dr. Lingyun Wu"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Dr. Paul Lee","Dr. Steven Richardson","Dr. Kaushik Desai","Dr. Linda Hiebert","Dr. Thomas Fisher"]},{"key":"dc:creator","label":"Author","values":["Untereiner, Ashley Anne"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2011-05-27T20:36:48Z","2013-01-04T04:33:30Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2012-06-24T08:00:00Z","2013-01-04T04:33:30Z"]},{"key":"dc:date.issued","label":"Date","values":["2011-05-01"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmacology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Masters"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science (M.Sc.)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Saskatchewan"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Hydrogen sulfide","Fructose-1 6-bisphosphatase","Vascular smooth muscle cells","Peroxisome proliferator-activated receptor-g","Methylglyoxal","Reactive oxygen species"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_US"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10388/etd-05272011-203648"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Methylglyoxal (MG) is a reactive glucose metabolite and a known causative factor for hypertension and diabetes. Hydrogen sulfide (H₂S), on the other hand, is a gasotransmitter with multifaceted physiological functions, including anti-oxidant and vasodilatory properties. The present study demonstrates that MG and H₂S can interact with and modulate each other's functions. Upon in vitro incubations, we found that MG and H₂S can directly interact to form three possible MG-H₂S adducts. Furthermore, the endogenous production level of MG or H₂S was significantly reduced in a concentration-dependent manner in rat vascular smooth muscle cells (A-10 cells) treated with NaHS, a H₂S 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 H₂S-generating enzyme in the vasculature. Moreover, H₂S 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⁻/⁻), mice with lower levels of vascular H₂S, 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⁻/⁻ 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⁻/⁻ 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⁻/⁻ mice. Likewise, FBPase-1 and -2 mRNA levels were also significantly down-regulated in aorta tissues from 14-16 week-old CSE⁻/⁻ 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 H₂S in regulating the rate of gluconeogenesis and MG formation. Overall, this unique study demonstrates the existence of a negative correlation between MG and H₂S in the vasculature. Further elucidation of this cross-talk phenomenon between MG and H₂S could lead to more elaborate and effective therapeutic regimens to combat metabolic syndrome and its related health complications."]},{"key":"dc:title","label":"Title","values":["Enhanced methylglyoxal formation in cystathionine γ-lyase knockout mice"]}]}],"canonical_facts":{"dc:contributor.advisor":["Dr. Lingyun Wu"],"dc:contributor.committeemember":["Dr. Paul Lee","Dr. Steven Richardson","Dr. Kaushik Desai","Dr. Linda Hiebert","Dr. Thomas Fisher"],"dc:creator":["Untereiner, Ashley Anne"],"dc:date.accessioned":["2011-05-27T20:36:48Z","2013-01-04T04:33:30Z"],"dc:date.available":["2012-06-24T08:00:00Z","2013-01-04T04:33:30Z"],"dc:date.issued":["2011-05-01"],"dc:description.abstract":["Methylglyoxal (MG) is a reactive glucose metabolite and a known causative factor for hypertension and diabetes. Hydrogen sulfide (H₂S), on the other hand, is a gasotransmitter with multifaceted physiological functions, including anti-oxidant and vasodilatory properties. The present study demonstrates that MG and H₂S can interact with and modulate each other's functions. Upon in vitro incubations, we found that MG and H₂S can directly interact to form three possible MG-H₂S adducts. Furthermore, the endogenous production level of MG or H₂S was significantly reduced in a concentration-dependent manner in rat vascular smooth muscle cells (A-10 cells) treated with NaHS, a H₂S 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 H₂S-generating enzyme in the vasculature. Moreover, H₂S 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⁻/⁻), mice with lower levels of vascular H₂S, 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⁻/⁻ 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⁻/⁻ 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⁻/⁻ mice. Likewise, FBPase-1 and -2 mRNA levels were also significantly down-regulated in aorta tissues from 14-16 week-old CSE⁻/⁻ 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 H₂S in regulating the rate of gluconeogenesis and MG formation. Overall, this unique study demonstrates the existence of a negative correlation between MG and H₂S in the vasculature. Further elucidation of this cross-talk phenomenon between MG and H₂S could lead to more elaborate and effective therapeutic regimens to combat metabolic syndrome and its related health complications."],"dc:identifier.uri":["https://hdl.handle.net/10388/etd-05272011-203648"],"dc:language.iso":["en_US"],"dc:subject":["Hydrogen sulfide","Fructose-1 6-bisphosphatase","Vascular smooth muscle cells","Peroxisome proliferator-activated receptor-g","Methylglyoxal","Reactive oxygen species"],"dc:title":["Enhanced methylglyoxal formation in cystathionine γ-lyase knockout mice"],"thesis:degree_discipline":["Pharmacology"],"thesis:degree_level":["Masters"],"thesis:degree_name":["Master of Science (M.Sc.)"],"thesis:institution_name":["University of Saskatchewan"]},"updated_at":"2026-07-24T04:26:49Z"}