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: Rudo F Mapanga, Uthra Rajamani, Nonkululeko Dlamini, Makhosazane Zungu-Edmondson, Roisin Kelly-Laubscher, Mohammed Shafiullah, Athiq Wahab, Mohamed Y Hasan, Mohamed A Fahim, Philippe Rondeau, Emmanuel Bourdon, M Faadiel Essop
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e47322 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23091615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Plant Extracts
• Reactive Oxygen Species
• Oleanolic Acid
• Proteasome Endopeptidase Complex

Topics

• Animals
• Apoptosis (drug effects)
• Cardiotonic Agents (isolation & purification, pharmacology)
• Cell Line
• Disease Models, Animal
• Heart (drug effects, physiopathology)
• Hyperglycemia (metabolism, physiopathology)
• Male
• Myocardial Contraction (drug effects)
• Myocardium (metabolism)
• Oleanolic Acid (isolation & purification, pharmacology)
• Plant Extracts (pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Syzygium (chemistry)