糖尿病对心肌缺血后适应预防心肌再灌注损伤作用的影响及药物干预
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摘要
心肌缺血后适应(myocardial ischemic postconditioning, MIPO)是在再灌注开始立刻给予短暂、多次、重复的心肌缺血与再灌注,然后再完全开放病变冠状动脉,能提高心肌对较长时间缺血的耐受性,减轻再灌注损伤以保护心肌。
本研究将观察缺血后适应在正常大鼠及糖尿病大鼠中发挥预防心肌缺血再灌注损伤作用的异同,明确缺血后适应保护的作用机制,并探讨在病理状态下如何通过药物干预恢复或唤醒被弱化或消失的缺血后适应保护作用。
研究结果表明:缺血后适应对于正常大鼠心肌再灌注损伤有保护作用,表现为心肌梗死面积减小及心肌酶释放减少、心脏血流动力学指标明显改善。PI3K-Akt信号通路在保护作用机制中起重要作用,免疫组化和western印迹分析显示缺血后适应的磷酸化Akt和GSK-3β表达增强。缺血后适应对于糖尿病大鼠离体心脏无保护作用,其磷酸化Akt、GSK-3表达减弱。糖尿病大鼠补充外源性锌(Zinc)后,缺血后适应预防再灌注损伤的作用得以恢复或唤醒,血流动力学指标改善和Akt、GSK-3β磷酸化水平增强。表明锌(Zinc)作为一种GSK-3β的直接或间接的抑制剂,可通过增强Akt磷酸化水平或直接抑制GSK-3β活性,使再灌注损伤救援激酶信号通路级联反应中下游物质GSK-3β磷酸化水平增高而失活,进而抑制心肌细胞线粒体通透性转换孔(mPTP)过度开放,保护缺血心肌免于再灌注损伤。
Coronary heart disease (CHD) is the leading cause of death in the world and represents one of the major burdens on healthcare systems today. Targeting those strategies that limit the damage sustained as a result of a lethal ischemic insult has been a major goal for many years.Reperfusion is the definitive treatment to salvage ischemic myocardium from infarction. A primary determinant of infarct size is the duration of ischemia. In myocardium that has not been irreversibly injured by ischemia, reperfusion induces additional injury in the area at risk. The heart has potent innate cardioprotective mechanisms against ischemia-reperfusion that reduce infarct size and other presentations of postischemic injury. In 1986, Murry et al. first introduced the concept of ischemic preconditioning (IPR) in which repetitive brief periods of ischemia protected the myocardium from a subsequent longer ischemic insult. Preconditioning succeeded in significantly reducing infarct size, preserve vascular endothelial function, and reduce apoptosis. Although preconditioning has been clinically successful, its use as a clinical cardioprotective strategy to attenuate the pathophysiological consequences (i.e., arrhythmias and infarction) of ischemia-reperfusion injury is limited by the inability to predict the onset of ischemia.
In 2003, Zhao et al first described that brief episodes of ischemia performed at the onset of reperfusion after a prolonged ischemia provided a powerful anti necrotic protection, named“Postconditioning”(IPO), IPO defined as brief intermittent cycles of ischemia alternating with reperfusion applied after the ischemic event, has been shown to reduce infarct size, in some cases equivalent to that observed with IPO. Although there are similarities in mechanisms of cardioprotection by these two interventions, there are key differences that go beyond simply exerting these mechanisms before or after ischemia. On the other hand, IPO is applied at the point of service in the hospital, where and when reperfusion is initiated. Initial clinical studies are in agreement with the success and extent to which IPO reduces infarct size and myocardial injury, even in the presence of multiple comorbidities.
Postconditioning has been shown to inhibit the mitochondrial permeability transition pore. Hence, postconditioning marshals a variety of endogenous mechanisms that operate at numerous levels and target a broad range of pathological mechanisms. The mechanism IPO protect of ischemic myocardial reperfusion injury is, After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. Recent study has demonstrated that serine9 phosphorylation of GSK-3βis required for cardioprotection by postconditioning and likely acts by inhibiting opening of the mPTP at the time of reperfusion in a CypD-independent way .Postconditioning inhibits opening of the mPTP and provides a powerful antiischemic protection.Clinical studies in patients with acute myocardial infarction have demonstrated that postconditioning was effective in reducing infarct size. Postconditioning indirectly supports the concept of reperfusion injury in animal models of ischaemia–reperfusion and in patients, and exerts cardioprotection.We studied cardioprotection of IPO indiabetic heart existence or no, and how to wake-up and recovery cardioprotection of IPO in diabetic heart.
Given the prevalence of ischaemic heart disease in diabetic patients, whether the diabetic heart is amenable to ischaemic postconditioning is an important unanswered question. Previous studies have demonstrated that postconditioning signals through the PI3K-Akt kinase pathway. Other studies have documented impaired PI3K-Akt signalling in the diabetic myocardium. We hypothesised that due to impaired signaling through the PI3K-Akt pathway, postconditioning does not protect the diabetic heart. Hearts isolated from the in-bred lean model of type II diabetes (High-fat diet+STZ induced rat) were randomised to either control or ischaemic postconditioning (IPost). Control hearts were mounted on a Langendorff apparatus and subjected to 30 min of myocardial ischaemia followed by either: (a) 10 min of reperfusion, at the end of which the myocardium at risk was analysed for Akt phosphorylation or (b) 120 min of reperfusion at the end of which myocardial infarct size was determined using tetrazolium staining. Hearts treated by IPost were subjected to 10 s episodes of alternate myocardial ischaemia/reperfusion applied at the end of the 30 min ischaemic period. Treatment with IPost did not reduce myocardial infarct size (45.65±4.8% in control versus 50.12±3.7% in IPost diabetic hearts; N = 10/group; P = NS). There was no difference in Akt phosphorylation between the two groups (51.5±4.6arbitrary units in control versus 54.1±4.2 arbitrary units in IPost diabetic hearts; N = 10/group; P = NS). And no difference in GSK-3βphosphorylation between the two groups (47.2±4.1arbitrary units in control versus 51.4±3.7 arbitrary units in IPost diabetic hearts; N = 10/group; P = NS). And, no improvement in hemodynamic parameters, include the HR, LVSP and +dp/dtmax. Exogenous zinc gived intraperitoneal injection in diabetic rats (ZnSO4 solution,50mg/Kg),and the action of IPO can be wake-up and recovery.show that improvement in hemodynamic parameters,and infart size reduced compared with the IPost heart of diabetic rats (31.10±3.4% VS 50.12±3.7%, p<0.01, n=10), There was Significant difference in Akt and GSK-3βphosphorylation between the two groups (67.6±3.4arbitrary units in Zinc+DM versus 54.1±4.2 arbitrary units in IPost diabetic hearts; N = 10/group; P <0.01 in Akt and 83.8±3.7arbitrary units in Zinc+DM versus 51.4±3.2 arbitrary units in IPost diabetic hearts; N = 10/group; P<0.01 in GSK-3β).
In conclusion, we have demonstrated that postconditioning was effective in reducing infarct size. Postconditioningpostconditioning does not protect the diabetic heart which may be due to insufficient Akt and GSK-3βactivation. Exogenous zinc gived in diabetic rats the action of IPO can be wake-up and recovery.This finding may have important implications on the utilisation of this cardioprotective intervention in diabetic patients with ischaemic heart disease. IPO increases phosphorylation of GSK-3βthrough a PI3-kinase–PKB-dependent pathway, since wortmannin blocks the IPO-induced phosphorylation of GSK-3β. The GSK-3βinhibitors, Zinc, mimices the cardioprotective effect of IPO, suggesting that inhibition of GSK-3βis protective in IPO. We conclude that GSK-3βis involved in the cardioprotective effect of IPO through a PI3-kinase–dependent pathway. These data indicate that pharmacological modulation of GSK-3βactivity could have utility for protecting the heart against ischemic injury.
本研究将观察缺血后适应在正常大鼠及糖尿病大鼠中发挥预防心肌缺血再灌注损伤作用的异同,明确缺血后适应保护的作用机制,并探讨在病理状态下如何通过药物干预恢复或唤醒被弱化或消失的缺血后适应保护作用。
研究结果表明:缺血后适应对于正常大鼠心肌再灌注损伤有保护作用,表现为心肌梗死面积减小及心肌酶释放减少、心脏血流动力学指标明显改善。PI3K-Akt信号通路在保护作用机制中起重要作用,免疫组化和western印迹分析显示缺血后适应的磷酸化Akt和GSK-3β表达增强。缺血后适应对于糖尿病大鼠离体心脏无保护作用,其磷酸化Akt、GSK-3表达减弱。糖尿病大鼠补充外源性锌(Zinc)后,缺血后适应预防再灌注损伤的作用得以恢复或唤醒,血流动力学指标改善和Akt、GSK-3β磷酸化水平增强。表明锌(Zinc)作为一种GSK-3β的直接或间接的抑制剂,可通过增强Akt磷酸化水平或直接抑制GSK-3β活性,使再灌注损伤救援激酶信号通路级联反应中下游物质GSK-3β磷酸化水平增高而失活,进而抑制心肌细胞线粒体通透性转换孔(mPTP)过度开放,保护缺血心肌免于再灌注损伤。
Coronary heart disease (CHD) is the leading cause of death in the world and represents one of the major burdens on healthcare systems today. Targeting those strategies that limit the damage sustained as a result of a lethal ischemic insult has been a major goal for many years.Reperfusion is the definitive treatment to salvage ischemic myocardium from infarction. A primary determinant of infarct size is the duration of ischemia. In myocardium that has not been irreversibly injured by ischemia, reperfusion induces additional injury in the area at risk. The heart has potent innate cardioprotective mechanisms against ischemia-reperfusion that reduce infarct size and other presentations of postischemic injury. In 1986, Murry et al. first introduced the concept of ischemic preconditioning (IPR) in which repetitive brief periods of ischemia protected the myocardium from a subsequent longer ischemic insult. Preconditioning succeeded in significantly reducing infarct size, preserve vascular endothelial function, and reduce apoptosis. Although preconditioning has been clinically successful, its use as a clinical cardioprotective strategy to attenuate the pathophysiological consequences (i.e., arrhythmias and infarction) of ischemia-reperfusion injury is limited by the inability to predict the onset of ischemia.
In 2003, Zhao et al first described that brief episodes of ischemia performed at the onset of reperfusion after a prolonged ischemia provided a powerful anti necrotic protection, named“Postconditioning”(IPO), IPO defined as brief intermittent cycles of ischemia alternating with reperfusion applied after the ischemic event, has been shown to reduce infarct size, in some cases equivalent to that observed with IPO. Although there are similarities in mechanisms of cardioprotection by these two interventions, there are key differences that go beyond simply exerting these mechanisms before or after ischemia. On the other hand, IPO is applied at the point of service in the hospital, where and when reperfusion is initiated. Initial clinical studies are in agreement with the success and extent to which IPO reduces infarct size and myocardial injury, even in the presence of multiple comorbidities.
Postconditioning has been shown to inhibit the mitochondrial permeability transition pore. Hence, postconditioning marshals a variety of endogenous mechanisms that operate at numerous levels and target a broad range of pathological mechanisms. The mechanism IPO protect of ischemic myocardial reperfusion injury is, After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. Recent study has demonstrated that serine9 phosphorylation of GSK-3βis required for cardioprotection by postconditioning and likely acts by inhibiting opening of the mPTP at the time of reperfusion in a CypD-independent way .Postconditioning inhibits opening of the mPTP and provides a powerful antiischemic protection.Clinical studies in patients with acute myocardial infarction have demonstrated that postconditioning was effective in reducing infarct size. Postconditioning indirectly supports the concept of reperfusion injury in animal models of ischaemia–reperfusion and in patients, and exerts cardioprotection.We studied cardioprotection of IPO indiabetic heart existence or no, and how to wake-up and recovery cardioprotection of IPO in diabetic heart.
Given the prevalence of ischaemic heart disease in diabetic patients, whether the diabetic heart is amenable to ischaemic postconditioning is an important unanswered question. Previous studies have demonstrated that postconditioning signals through the PI3K-Akt kinase pathway. Other studies have documented impaired PI3K-Akt signalling in the diabetic myocardium. We hypothesised that due to impaired signaling through the PI3K-Akt pathway, postconditioning does not protect the diabetic heart. Hearts isolated from the in-bred lean model of type II diabetes (High-fat diet+STZ induced rat) were randomised to either control or ischaemic postconditioning (IPost). Control hearts were mounted on a Langendorff apparatus and subjected to 30 min of myocardial ischaemia followed by either: (a) 10 min of reperfusion, at the end of which the myocardium at risk was analysed for Akt phosphorylation or (b) 120 min of reperfusion at the end of which myocardial infarct size was determined using tetrazolium staining. Hearts treated by IPost were subjected to 10 s episodes of alternate myocardial ischaemia/reperfusion applied at the end of the 30 min ischaemic period. Treatment with IPost did not reduce myocardial infarct size (45.65±4.8% in control versus 50.12±3.7% in IPost diabetic hearts; N = 10/group; P = NS). There was no difference in Akt phosphorylation between the two groups (51.5±4.6arbitrary units in control versus 54.1±4.2 arbitrary units in IPost diabetic hearts; N = 10/group; P = NS). And no difference in GSK-3βphosphorylation between the two groups (47.2±4.1arbitrary units in control versus 51.4±3.7 arbitrary units in IPost diabetic hearts; N = 10/group; P = NS). And, no improvement in hemodynamic parameters, include the HR, LVSP and +dp/dtmax. Exogenous zinc gived intraperitoneal injection in diabetic rats (ZnSO4 solution,50mg/Kg),and the action of IPO can be wake-up and recovery.show that improvement in hemodynamic parameters,and infart size reduced compared with the IPost heart of diabetic rats (31.10±3.4% VS 50.12±3.7%, p<0.01, n=10), There was Significant difference in Akt and GSK-3βphosphorylation between the two groups (67.6±3.4arbitrary units in Zinc+DM versus 54.1±4.2 arbitrary units in IPost diabetic hearts; N = 10/group; P <0.01 in Akt and 83.8±3.7arbitrary units in Zinc+DM versus 51.4±3.2 arbitrary units in IPost diabetic hearts; N = 10/group; P<0.01 in GSK-3β).
In conclusion, we have demonstrated that postconditioning was effective in reducing infarct size. Postconditioningpostconditioning does not protect the diabetic heart which may be due to insufficient Akt and GSK-3βactivation. Exogenous zinc gived in diabetic rats the action of IPO can be wake-up and recovery.This finding may have important implications on the utilisation of this cardioprotective intervention in diabetic patients with ischaemic heart disease. IPO increases phosphorylation of GSK-3βthrough a PI3-kinase–PKB-dependent pathway, since wortmannin blocks the IPO-induced phosphorylation of GSK-3β. The GSK-3βinhibitors, Zinc, mimices the cardioprotective effect of IPO, suggesting that inhibition of GSK-3βis protective in IPO. We conclude that GSK-3βis involved in the cardioprotective effect of IPO through a PI3-kinase–dependent pathway. These data indicate that pharmacological modulation of GSK-3βactivity could have utility for protecting the heart against ischemic injury.
引文
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