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.
Highlights
The dramatic surge in diabetes during the past few decades constitutes a major threat to human health in developed and developing nations [1,2]
Our data show significantly increased reactive oxygen species (ROS) levels in heart cells that were cultured under high glucose conditions (Figure 1)
For the current study we explored whether oleanolic acid (OA) acts as a novel cardioprotective factor in response to ischemia-reperfusion under hyperglycemic conditions
Summary
The dramatic surge in diabetes during the past few decades constitutes a major threat to human health in developed and developing nations [1,2]. Stress-induced, acute hyperglycemia in non-diabetic patients with acute myocardial infarction is associated with increased in-hospital deaths [7,8]. Previous studies revealed dysfunctional UPS with hyperglycemia, linked to greater inflammation and attenuated cardiac function at baseline and in response to ischemia-reperfusion [10,15]. It remains unclear whether increased or decreased UPS is detrimental with hyperglycemia and/or in response to ischemiareperfusion. Pye et al [16] found that myocardial reperfusion injury is reduced by proteasomal inhibitors, while others determined that UPS overactivity may enhance the risk of complication during myocardial ischemia in diabetic patients [10]. Additional studies are required to determine the mechanisms underlying dysfunctional UPS in the heart under these conditions
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