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.

Biologically Active Triterpenoids and Their Cardioprotective and Anti- Inflammatory Effects

“…Similar to its isomer ursolic acid that is found abundantly in apple peels, oleanolic acid can also confer numerous pharmacological properties and have cardioprotective effects. For example, OA was previously found to inhibit COX-2 enzyme activity by 10% [53]; inhibition of COX-2 enzyme activity can reduce the risk of inflammation. Various recent studies have found the effect of OA to be beneficial to the heart; the study by Marquez-Martin et al (2006) concluded that in human mononuclear cells, OA promotes an anti-inflammatory cytokine profile and interferes with the generation of cardiac-specific antibodies, thereby developing and establishing the prevention and treatment of experimental autoimmune myocarditis (EAM) [54][55][56][57].…”

“…VEGF action on VSMC is essential for collateral vessel formation, and poor collateral vessel formation has been proposed to lead to the pathogenesis of obesity vascular complications [71]. Similarly, Mapanga et al (2012) concluded that OA treatment in streptozotocin diabetic rats resulted in improved heart function and cardioprotection through the reduction of oxidative stress, HBP flux, and apoptosis in heart cells, thereby offering a potential novel therapeutic intervention to treat patients with associated cardiovascular complications [71].…”

“…Grape products similarly had triterpenoid compounds, mainly OA, that activated mechanisms that reduced oxidative stress, HBP flux, and apoptosis through increased myocardial level of Nrf2 and Nrf2 nuclear translocation [53,54]. OA also mediated the urinary F2-isoprostanes regulating mechanisms, superoxide production mechanisms, serum cholesterol level reducing mechanisms, and mechanisms that decreased the low-density lipoprotein susceptibility to oxidation; these mechanisms all conferred beneficial effects in CVD prevention [34][35][36][37][38][39][40][41][42].…”

Oleanolic acid alleviated pressure overload-induced cardiac remodeling

“…Previous studies have demonstrated additional interactions of OA with regulatory signaling pathways like PI3K/Akt, mTOR [12], TGF-b [13], MAPKs, and NF-kB [14], all of which tangled in the regulation of physiology and pathology stress stimulation. Some of these studies had also shown that OA could regulate the homeostasis of cardiovascular system [8,9,15]. However, it was not clear whether OA could directly prevent the process of malignant cardiac remodeling.…”

“…OA ameliorated experimental autoimmune myocarditis by promoting the production of anti-inflammatory cytokines and inhibiting the production of the proinflammatory and pro-fibrotic cytokines [8]. Treatment of OA improved the heart function and blunted high-glucoseinduced oxidative stress and apoptosis in diabetic mice [9]. However, its effect on cardiac hypertrophy has not yet been addressed.…”