title: Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.
abstract: The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R) injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control), Hesperidin (100 mg/kg/day; IR-Hesperidin), GW9962 (PPAR-γ receptor antagonist), or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD) coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt) as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of hesperidin in I/R model in rats.
authors.affiliation: School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan, India; Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India; Department of Pharmaceutics and Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India.
authors.forename: Yogeeta O
authors.initials: YO
authors.lastname: Agrawal
authors.affiliation: School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan, India.
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Sharma
authors.affiliation: School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan, India.
authors.forename: Birendra
authors.initials: B
authors.lastname: Shrivastava
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Shreesh
authors.initials: S
authors.lastname: Ojha
authors.affiliation: Sunil's Daibetes and Research Center, Nagpur, Maharashtra, India.
authors.forename: Harshita M
authors.initials: HM
authors.lastname: Upadhya
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Dharamvir Singh
authors.initials: DS
authors.lastname: Arya
authors.affiliation: Department of Pharmaceutics and Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India.
authors.forename: Sameer N
authors.initials: SN
authors.lastname: Goyal
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006569:Hesperidin / Q000494:pharmacology / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002316:Cardiotonic Agents; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D006569:Hesperidin; D052279:Creatine Kinase, MB Form