title: Oleanolic acid: a novel cardioprotective agent that blunts hyperglycemia-induced contractile dysfunction.
abstract: Diabetes constitutes a major health challenge. Since cardiovascular complications are common in diabetic patients this will further increase the overall burden of disease. Furthermore, stress-induced hyperglycemia in non-diabetic patients with acute myocardial infarction is associated with higher in-hospital mortality. Previous studies implicate oxidative stress, excessive flux through the hexosamine biosynthetic pathway (HBP) and a dysfunctional ubiquitin-proteasome system (UPS) as potential mediators of this process. Since oleanolic acid (OA; a clove extract) possesses antioxidant properties, we hypothesized that it attenuates acute and chronic hyperglycemia-mediated pathophysiologic molecular events (oxidative stress, apoptosis, HBP, UPS) and thereby improves contractile function in response to ischemia-reperfusion. We employed several experimental systems: 1) H9c2 cardiac myoblasts were exposed to 33 mM glucose for 48 hr vs. controls (5 mM glucose); and subsequently treated with two OA doses (20 and 50 µM) for 6 and 24 hr, respectively; 2) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) for 60 min, followed by 20 min global ischemia and 60 min reperfusion ± OA treatment; 3) In vivo coronary ligations were performed on streptozotocin treated rats ± OA administration during reperfusion; and 4) Effects of long-term OA treatment (2 weeks) on heart function was assessed in streptozotocin-treated rats. Our data demonstrate that OA treatment blunted high glucose-induced oxidative stress and apoptosis in heart cells. OA therapy also resulted in cardioprotection, i.e. for ex vivo and in vivo rat hearts exposed to ischemia-reperfusion under hyperglycemic conditions. In parallel, we found decreased oxidative stress, apoptosis, HBP flux and proteasomal activity following ischemia-reperfusion. Long-term OA treatment also improved heart function in streptozotocin-diabetic rats. These findings are promising since it may eventually result in novel therapeutic interventions to treat acute hyperglycemia (in non-diabetic patients) and diabetic patients with associated cardiovascular complications.
authors.affiliation: Cardio-Metabolic Research Group, Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Rudo F
authors.initials: RF
authors.lastname: Mapanga
authors.forename: Uthra
authors.initials: U
authors.lastname: Rajamani
authors.forename: Nonkululeko
authors.initials: N
authors.lastname: Dlamini
authors.forename: Makhosazane
authors.initials: M
authors.lastname: Zungu-Edmondson
authors.forename: Roisin
authors.initials: R
authors.lastname: Kelly-Laubscher
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shafiullah
authors.forename: Athiq
authors.initials: A
authors.lastname: Wahab
authors.forename: Mohamed Y
authors.initials: MY
authors.lastname: Hasan
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Fahim
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondeau
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourdon
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D009828:Oleanolic Acid / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D027842:Syzygium / Q000737:chemistry
chemical_list: D002316:Cardiotonic Agents; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; D046988:Proteasome Endopeptidase Complex