Sirt1 Activation by Post-ischemic Treatment With Lumbrokinase Protects Against Myocardial Ischemia-Reperfusion Injury

Abstract

Lumbrokinase is used as an oral supplement to support and maintain healthy cardiovascular function, and to treat cardiovascular diseases in clinical for more than 10 years. Up until now, the mechanism of the cardioprotective effects of post-ischemic treatment with lumbrokinase has remained unclear. We therefore investigated the signaling pathways involved in the amelioration of myocardial ischemia-reperfusion (I-R) injury in rats treated with lumbrokinase 20 min after myocardial ischemia. Compared to vehicle-treated rats, post-ischemic treatment with lumbrokinase was associated with significant reductions in myocardial I-R-induced arrhythmias and myocardial damage, and an improvement in cardiac function. Moreover, lumbrokinase significantly upregulated levels of silent information regulator 1 (Sirt1). In addition, lumbrokinase significantly increased manganese-dependent superoxide dismutase expression, decreased Cleaved-Caspase-3 expression, and induced deacetylation of FoxO1. On the other hand, lumbrokinase also significantly downregulated levels of succinate dehydrogenase, cytochrome c oxidase, nuclear factor kappa B (NF-κB) and elevated levels of microtubule-associated protein light chain 3. Notably, the cardioprotective effects of lumbrokinase were abolished by administration of the specific Sirt1 inhibitor EX527. These findings demonstrate that post-ischemic treatment with lumbrokinase attenuates myocardial I-R injury through the activation of Sirt1 signaling, and thus enhances autophagic flux and reduces I-R-induced oxidative damage, inflammation and apoptosis.

SIRT1/SIRT3 Modulates Redox Homeostasis during Ischemia/Reperfusion in the Aging Heart

“…FoxO1, an important forhead transcription factor in the cardiovascular system [ 109 ], participates in the process of substrate metabolism and cell proliferation [ 110 ]. SIRT1 also has the capacity to deacetylase FoxO1 and repress its transcriptional activity during I/R, which acts as a pivotal part in controlling the increase of manganese superoxide dismutase (MnSOD) and inhibiting oxidative stress in cardiac myocytes [ 111 , 112 ] ( Figure 1 ). Consistently, the upregulation of FoxO1 was significantly enhanced with the increased expression of antioxidant MnSOD in cardiac-specific SIRT1 transgenic mice under ischemic stress [ 111 , 112 ].…”

Rno-microRNA-30c-5p promotes myocardial ischemia reperfusion injury in rats through activating NF-κB pathway and targeting SIRT1

“…Yu et al 31 have indicated that melatonin ameliorates IR-induced oxidative stress and endoplasmic reticulum stress via activating SIRT1 signaling in type 2 diabetic rats. Wang et al 32 have proved that post-ischemic treatment with lumbrokinase attenuates myocardial IR injury through the activation of Sirt1 signaling. Lin et al 33 have demonstrated that the activation of SIRT1/Nrf2 signaling induced by Rutin contributes to the reduced oxidative stress and apoptosis of cardiomyocytes in rats with myocardial IR injury.…”

Deficiency of Interleukin-36 Receptor Protected Cardiomyocytes from Ischemia-Reperfusion Injury in Cardiopulmonary Bypass

“…The activity of SIRT1 deacetylase is significantly increased during stress. Deacetylation of SIRT1 downregulated transcriptional function of p53 to induce cell survival [16,17]. An increase in SIRT1 deacetylase activity can inhibit stress-induced cell apoptosis and oxidative stress injury via activation of SIRT1-FOXO1/p53 signaling [18].…”