Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor γ agonist improve vascular function and decrease renal injury in hypertensive obese rats.
Cardiometabolic syndrome occurs with obesity and consists of pathophysiological factors that increase the risk for cardiovascular events. Soluble epoxide hydrolase inhibition (sEHi) is a novel therapeutic approach that exerts renal and cardiovascular protection. Although sEHi as a therapeutic approach is promising, it could be more effective for the treatment of cardiometabolic syndrome when combined with peroxisome proliferator activated receptor γ (PPARγ) agonists. We hypothesized that the PPARγ agonist, rosiglitazone in combination with a sEHi (tAUCB) will provide synergistic actions to decrease blood pressure, improve vascular function, decrease inflammation, and prevent renal damage in spontaneously hypertensive obese rats (SHROB). SHROB were treated with rosiglitazone, tAUCB or the combination of tAUCB and rosiglitazone for four-weeks and compared with spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Blood pressure increased in SHROB (164 ± 7 mmHg) and decreased 10 mmHg when treated with rosiglitazone, tAUCB, or tAUCB and rosiglitazone. Mesenteric artery dilation to the K(ATP) channel opener pinacidil was attenuated in SHROB (E(Max) = 77 ± 7%), compared with WKY (E(Max) = 115 ± 19) and SHR (E(Max) = 93 ± 12%). Vasodilation to pinacidil was improved by rosiglitazone (E(Max) = 92 ± 14%) but not tAUCB. Renal macrophage infiltration increased in SHROB and significantly decreased with rosiglitazone or tAUCB and rosiglitazone treatment. Albuminuria was increased in SHROB (90 ± 20 mg/d) and was significantly decreased by the combination of tAUCB and rosiglitazone (37 ± 9 mg/d). Glomerular injury in SHROB was also significantly decreased by tAUCB and rosiglitazone. These results indicate that even though sEHi or PPARγ agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome.
Department of Pharmacology & Toxicology and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. jdimig@mcw.edu
John D
JD
Imig
Katie A
KA
Walsh
Md Abdul
MA
Hye Khan
Tasuku
T
Nagasawa
Mary
M
Cherian-Shaw
Sean M
SM
Shaw
Bruce D
BD
Hammock
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000293:injuries* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000077154:Rosiglitazone; D013045:Species Specificity; D013577:Syndrome; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004851:Epoxide Hydrolases