title: Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin.
abstract: This study tested the hypothesis that in diabetic arteries, cyclooxygenase (COX)-1 mediates endothelial prostacyclin (PGI2) synthesis, which evokes vasoconstrictor activity under the pathological condition. Non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1(-/-) mice) using a high-fat diet in combination with streptozotocin injection. In vitro analyses were performed 3 mo after. Results showed that in diabetic aortas, the endothelial muscarinic receptor agonist ACh evoked an endothelium-dependent production of the PGI2 metabolite 6-keto-PGF1α, which was abolished in COX-1(-/-) mice. Meanwhile, COX-1 deficiency or COX-1 inhibition prevented vasoconstrictor activity in diabetic abdominal aortas, resulting in enhanced relaxation evoked by ACh. In a similar manner, COX-1 deficiency increased the relaxation evoked by ACh in nitric oxide synthase-inhibited diabetic renal arteries. Also, in diabetic abdominal aortas and/or renal arteries, both PGI2 and the COX substrate arachidonic acid evoked contractions similar to those of nondiabetic mice. However, the contraction to arachidonic acid, but not that to PGI2, was abolished in vessels from COX-1(-/-) mice. Moreover, we found that 3 mo after streptozotocin injection, systemic blood pressure increased in diabetic C57BL/6 mice but not in diabetic COX-1(-/-) mice. These results explicitly demonstrate that in the given arteries from non-insulin-dependent diabetic mice, COX-1 remains a major contributor to the endothelial PGI2 synthesis that evokes vasoconstrictor activity under the pathological condition. Also, our data suggest that COX-1 deficiency prevents or attenuates diabetic hypertension in mice, although this could be related to the loss of COX-1-mediated activities derived from both vascular and nonvascular tissues.
authors.affiliation: Cardiovascular Research Center, Shantou University Medical College, Shantou, China; and.
authors.forename: Ningxia
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Cardiovascular Research Center, Shantou University Medical College, Shantou, China; and.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Central Laboratory, Shantou University Medical College, Shantou, China.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Luo
authors.affiliation: Cardiovascular Research Center, Shantou University Medical College, Shantou, China; and.
authors.forename: Yingzhan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Shantou University Medical College, Shantou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center, Shantou University Medical College, Shantou, China; and.
authors.forename: Shasha
authors.initials: S
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center, Shantou University Medical College, Shantou, China; and zhouyingbi35@gmail.com.
authors.forename: Yingbi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D001794:Blood Pressure; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048909:Diabetes Complications / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018721:Muscarinic Agonists; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D000109:Acetylcholine
keywords: arachidonic acid; contraction; diabetes; metabolism; thromboxane prostanoid receptors