Abstract
Luteolin has been reported to attenuate ischemia/reperfusion (I/R) injury in the diabetic heart through endothelial nitric oxide synthase- (eNOS-) related antioxidative response. Though the nuclear factor erythroid 2-related factor 2 (Nrf2) is regarded as a key endogenous factor to reduce diabetic oxidative stress, whether luteolin reduces cardiac I/R injury in the diabetic heart via enhancing Nrf2 function needs to be clarified. We hypothesized that pretreatment with luteolin could alleviate cardiac I/R injury in the diabetic heart by affecting the eNOS/Nrf2 signaling pathway. The diabetic rat was produced by a single injection of streptozotocin (65 mg/kg, i.p.) for 6 weeks, and then, luteolin (100 mg/kg/day, i.g.), eNOS inhibitor L-NAME, or Nrf2 inhibitor brusatol was administered for the succedent 2 weeks. After that, the isolated rat heart was exposed to 30 min of global ischemia and 120 min of reperfusion to establish I/R injury. Luteolin markedly ameliorated cardiac function and myocardial viability; upregulated expressions of heme oxygenase-1, superoxide dismutase, glutathione peroxidase, and catalase; and reduced myocardial lactate dehydrogenase release, malondialdehyde, and 8-hydroxydeoxyguanosine in the diabetic I/R heart. All these ameliorating effects of luteolin were significantly reversed by L-NAME or brusatol. Luteolin also markedly reduced S-nitrosylation of Kelch-like ECH-associated protein 1 (Keap1) and upregulated Nrf2 and its transcriptional activity. This effect of luteolin on Keap1/Nrf2 signaling was attenuated by L-NAME. These data reveal that luteolin protects the diabetic heart against I/R injury by enhancing eNOS-mediated S-nitrosylation of Keap1, with subsequent upregulation of Nrf2 and the Nrf2-related antioxidative signaling pathway.
Highlights
In 2017, about 425 million adults aged 20-79 years had diabetes, and these numbers were expected to increase to 629 million by 2045 [1]
These data suggest that the loss of endogenous protective mechanisms either by hyperglycemia or by diabetes itself may result in the poor prognosis in diabetic subjects after myocardial I/R events and vigorous therapeutic strategies targeting I/R injury are required to benefit this population
8-week point, (2) activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidative function was essential for this action of luteolin as proved by the evidence that brusatol, an inhibitor of Nrf2, reduced the cardioprotective effect of luteolin, and (3) luteolin protected the diabetic heart against I/R injury through S-nitrosylation of Kelch-like ECH-associated protein 1 (Keap1) and activation of Nrf2 as demonstrated by the evidence that the eNOS inhibitor L-NAME decreased the S-nitrosylation of Keap1, Nrf2 function, and cardioprotection induced by luteolin (Figure 6)
Summary
In 2017, about 425 million adults aged 20-79 years had diabetes, and these numbers were expected to increase to 629 million by 2045 [1]. Ischemic conditioning and agents that protect the heart against ischemia/reperfusion (I/R) injury in nondiabetic subjects are mostly resisted in diabetic animals and patients [5]. Defective intracellular antioxidase production and activity, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), contributes to increased oxidative stress in diabetes [7]. Such a higher basal level of oxidative stress causes protein carboxylation, lipid peroxidation, and DNA damage, leading to cell
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