心肌去乙酰化酶SIR33对缺血／再灌注小鼠心律失常的影响

目的探讨心肌线粒体去乙酰化酶SIRT3对急性缺血再灌注（I／R）所致心律失常的影响。方法：以24只SIRT3基因敲除型小鼠为实验对象,用24只野生型小鼠为对照,两种小鼠均随机各分为对照组、假手术组、I／R模型组及I／R＋烟酰胺腺嘌呤二核苷酸（NAD＋）治疗组,每组6只小鼠（rt=6）。采用冠脉左前降支结扎缺血30 min再灌注2 h建立在体大鼠急性心肌I／R模型,于术中监测心电指标。取心肌组织检测SIRT3、锰超氧化物歧化酶（MnSOD）和过氧化氢酶（Catalase）蛋白的表达和心肌内氧自由基（ROS）的水平。结果：与野生型对照小鼠相比,SIRT3基因敲除型小鼠心肌中SIRT3、MnSOD和Catalase蛋白表达的水平显著降低。心律失常评分的结果显示,SIRT3基因敲除型小鼠的假手术组即可观察到心律失常。SIR13基因敲除可导致小鼠心肌I／R所致心律失常显著加重（与野生型模型组相比,P〈0-05）。心肌I／R后,SIRT3基因敲除型小鼠心肌中ROS的增加程度明显高于野生型模型组小鼠（P〈0-05）。预先采用NAD＋治疗,可显著提高野生型I／R小鼠心肌SIRT3的活性（与野生型小鼠模型组相比,P〈0-05）,显著增加心肌MnSOD的活性,进而有效地抑制I／R小鼠心肌中ROS的水平,有效缓解I／R所致心律失常（与野生型小鼠模型组相比,均P〈0-05）。但是,SIR73基因敲除后,NAD＋治疗引起的上述心肌保护作用基本消失。结论：心肌中SIRT3表达的降低可能是加重心肌I／R过程中氧化应激损伤并促发心律失常的重要机制。SIRT3正常活性的维持有助于对抗心肌I／R损伤（MIRI）的发生。     

心肌缺血/再灌损伤时TXNIP表达水平升高并增加心肌自噬

目的 探讨心肌缺血/再灌注（MI/R）时硫氧还蛋白相互结合蛋白（TXNIP）表达及对心肌细胞自噬水平的影响。 方法 构建TXNIP敲除鼠及TXNIP过表达小鼠,制作上述小鼠MI/R模型,观察MI/R后心肌TXNIP表达水平是否与心肌损伤及自噬有关。 结果 与假手术组（Sham）小鼠相比,小鼠心肌TXNIP表达水平在缺血及再灌注损伤过程中持续升高（P<0.01）。在小鼠MI/R后,心脏超声证实与野生型（WT）小鼠相比,TXNIP过表达小鼠LVEF（%）值更低（P<0.05）;伊文氏蓝/TTC染色同样证实TXNIP过表达小鼠心肌梗死面积更大（P<0.05）。而TXNIP敲除鼠MI/R后心脏LVEF（%）值（P<0.05）及心肌梗死面积（P<0.05）均较WT小鼠显著减轻。通过免疫印迹（LC3Ⅱ/LC3I及P62表达）及电子显微镜观察自噬小体检测发现,相比WT小鼠,TXNIP敲除小鼠心肌自噬程度更轻（P<0.05）,TXNIP过表达小鼠则心肌自噬程度更重（P<0.05）。 结论 上述结果证实了在MI/R后TXNIP升高导致心脏功能的降低,心肌梗死面积的增加及心肌细胞自噬的增多。     

FoxO1变化对糖尿病小鼠心肌缺血/再灌注损伤的影响

目的:观察心肌中插头转录因子O1（FoxO1）在糖尿病（DM）小鼠心肌中表达量变化及对小鼠心肌缺血/再灌注（I/R）损伤的影响。方法: 将90只健康雄性Swiss小鼠随机分为5组:假手术（Sham）组、I/R组、DM+Sham组、DM+I/R组及DM+FoxO1SiRNA+I/R组,每组18只。采用高糖高脂饮食加链脲菌素(Streptozocin,STZ)腹腔注射诱导建立DM小鼠模型。采用FoxO1SiRNA心肌点注射下调心肌FoxO1表达。心肌I/R损伤模型的建立,采用结扎心脏冠状动脉左前降支30 min后再灌注方案实施。心肌再灌注3 h后,用原位缺口末端标法(TUNEL)检测心肌细胞凋亡。用ELISA法检测心肌中 Caspase-3的活性。用Western blot法检测心肌中FoxO1的表达量。心肌再灌注24 h后,用2,3,5-三苯基氯化四氮唑（TTC）染色法检测心肌梗死（MI）的面积。结果: 与Sham组比较,DM+Sham组心肌中FoxO1的表达量明显增高（P<0.01）。与I/R组比,DM+I/R组MI的面积增大（P<0.05）,心肌细胞凋亡数量及Caspase-3活性明显增加（P<0.01）。与DM+I/R组相比,DM+FoxO1SiRNA+I/R组心肌FoxO1的表达量下调（P<0.05）,MI面积及Caspase-3的活性减小（P<0.05）,心肌细胞凋亡数量减少（P<0.01）。结论: DM小鼠心肌中FoxO1表达量的增加可加重心肌I/R损伤;而下调心肌中FoxO1的表达量后,心肌I/R损伤减轻。     

间歇有氧运动训练改善肥胖小鼠缺血后心脏功能恢复

目的 探讨有氧间歇运动训练（AIT）对高脂饮食诱导的肥胖小鼠心肌缺血再灌注（MI/R）损伤的影响和相关机制。 方法 30只2月龄C57小鼠随机分为:正常对照组;高脂饮食组;高脂饮食间歇训练组。喂养12周后,建立急性MI/R模型（缺血30 min,再灌注4 h）。于再灌注结束后不同时间点采用超声心动仪检测心脏功能,Western blot法检测心脏相关信号表达。 结果 与正常对照组相比,12周高脂饮食喂养导致小鼠肥胖,体质量显著增加（P<0.05）;AIT可有效降低高脂饮食肥胖小鼠的体质量,增加心脏质量/胫骨长度比率（P<0.05）;与正常对照组相比,高脂饮食肥胖小鼠MI/R损伤显著加重（P<0.05）;AIT可有效减轻肥胖小鼠心肌损伤,减小心肌梗死面积和血清LDH水平（均P<0.05）;AIT还显著改善MI/R后心肌功能恢复,有效提高左室射血分数（EF）和左室短轴缩短率（FS）（均P<0.05）。与高脂饮食组相比,AIT可显著增强高脂饮食肥胖小鼠心肌线粒体SIRT3和MnSOD表达,减少高脂饮食组MI/R心肌组织氧化应激（均P<0.05）。 结论 AIT可有效提高高脂饮食肥胖小鼠心肌线粒体SIRT3和MnSOD表达,增加线粒体抗氧化酶活性,进而减轻肥胖小鼠的MI/R损伤,促进缺血后心脏功能恢复。     

间歇有氧运动训练上调SIRT3改善衰老心肌线粒体功能

目的 探讨间歇有氧运动训练（AIT）对调节SIRT3介导的抗氧化酶系统改善老年小鼠心肌线粒体功能的影响。方法 采用C57小鼠（20月龄）20只,随机分为AIT组和非运动组,每组10只。以成年野生型C57小鼠非运动组(4月龄,10只)为对照组。建立间歇有氧运动训练12周小鼠模型,跑台训练由3部分构成:10 min热身运动,7 min间歇训练（4 min高强度和3 min低强度训练）及1 min冷却。每日训练1 h,每周训练5 d,训练时间为12周。应用蛋白免疫印迹法(Western blot)检测心肌线粒体抗氧化酶相关蛋白的表达。结果 AIT显著上调衰老心肌中线粒体去乙酰化酶sirtuin-3（SIRT3）表达水平,提高AMP依赖的蛋白激酶(AMPK)的磷酸化水平(P<0.05);AIT可改善老年组小鼠心肌线粒体抗氧化酶(MnSOD、Catalase)的活性,有效减少衰老心肌脂质过氧化损伤(P<0.05);AIT训练显著提高衰老心肌线粒体生物合成能力改善了线粒体的功能(均P<0.05)。结论 有氧间歇运动训练可有效地上调衰老小鼠心肌细胞SIRT3水平,有效提高衰老小鼠心肌线粒体功能,其机制可能与激活心肌SIRT3所介导的抗氧化酶系统有关。     

衰老心肌缺血/再灌注损伤增加的新机制—程序性坏死的关键作用

目的 探讨程序性坏死（necroptosis）在衰老心肌缺血/再灌注(I/R)损伤中的关键作用。 方法 成年（ 3~4月龄）和老龄（ 22~24月龄）雄性C57BL/6小鼠20只各随机分为对照组与I/R组,建立小鼠急性心肌I/R模型（缺血30 min再灌注4 h）。再灌注结束后,取心肌组织并分别应用蛋白质免疫印迹法（Western blot）和免疫共沉淀法（Co-Immunoprecipitation;Co-IP）检测necroptosis标志蛋白的表达及其修饰变化。结果 与成年心肌相比,necroptosis的标志蛋白RIP1、RIP3在衰老心肌中的表达均升高（P<0.05）,necroptosis的调节蛋白去乙酰化酶SIRT2的表达及活性也显著升高（P<0.05）,RIP1的去乙酰化水平显著升高（P<0.05）。给予小剂量necroptosis抑制剂Necrostatin-1(Nec-1)处理,可以显著减少衰老心肌I/R梗死面积（P<0.05）。结论 本研究发现在衰老心肌I/R损伤中necroptosis显著增加,表明necroptosis可能在衰老心肌缺血损伤中有重要作用。     

成纤维细胞特异敲除转录因子ATF3基因的小鼠模型构建

目的:构建成纤维细胞特异敲除转录因子ATF3基因的小鼠模型。方法:利用胚胎显微注射法构建在ATF3基因携带loxP位点的小鼠(ATF3~(fl/fl)),以成纤维细胞细胞特异性表达的Col1a2-Cre介导ATF3条件性敲除,筛选出成纤维细胞条件性敲除ATF3的小鼠(Col1a2-ERCre:ATF3~(fl/fl));取鼠尾DNA进行PCR鉴定基因型,腹腔注射他莫昔芬诱导该基因敲除;12只敲除小鼠和12只同窝野生型小鼠各分为心脏缺血再灌注(I/R)组和假手术(sham)组,术后2h取心脏组织研磨后流式细胞分选成纤维细胞,进而提取mRNA并反转为cDNA,采用实时荧光定量PCR检测ATF3的表达;另取4只敲除小鼠和4只同窝野生型小鼠复制I/R模型,术后6h取心脏组织进行免疫荧光染色,观察成纤维细胞ATF3表达。结果:鼠尾DNA PCR鉴定基因型结果显示Cre基因型为阳性,ATF3 loxP基因型为纯合阳性;与假手术组相比,野生型小鼠术后心脏成纤维细胞ATF3表达明显升高[(0.02534±0.002654)vs.(0.5982±0.03495),P0.0001],与术后野生型小鼠相比,术后条件性敲除组心脏成纤维细胞ATF3表达明显降低[(0.5982±0.03495)vs.(0.06456±0.005704),P0.0001];免疫荧光共定位染色显示野生型小鼠心脏成纤维细胞ATF3蛋白表达,条件性敲除小鼠ATF3蛋白未见表达。结论:成纤维细胞特异敲除ATF3小鼠构建成功,为进一步实验奠定基础。     

RIP3-CaMKII通路激活程序性坏死在糖尿病心肌缺血/再灌注损伤中的作用

目的 本研究旨在探讨受体相互作用蛋白(RIP)3-钙离子/钙调蛋白依赖蛋白激酶(CaMK)II通路激活的程序性坏死(necroptosis)在糖尿病心肌缺血/再灌注(I/R)损伤中的作用。方法 成年(3~4月龄)雄性C57BL/6小鼠70只，随机分为正常组（n=30）与STZ诱导的糖尿病组（n=40）。随后采用小鼠急性心肌I/R在体模型(缺血30 min再灌注4 h)。再灌注后取心肌组织，一部分应用Western blot法检测RIP3-CaMKII信号的表达及修饰变化，另一部分做冰冻切片组织免疫荧光，通过伊文氏蓝阳性区域的面积占比反映程序性坏死的程度。结果 与正常组相比，糖尿病组小鼠I/R后心肌程序性坏死程度显著升高（P<0.05）；在糖尿病I/R心肌中RIP3表达水平和磷酸化CaMKII水平较正常组I/R心肌均显著升高（P<0.05）。对糖尿病小鼠再灌注前给予CaMKII抑制剂KN-93处理可以显著降低糖尿病心肌I/R后的程序性坏死比例（P<0.05）。结论 本研究证实在糖尿病心肌I/R损伤中程序性坏死显著增加，提示RIP3-CaMKII信号增强引发心肌程序性坏死在糖尿病心肌缺血易损中起重要作用。     

下调NAD（P）H氧化酶4加重缺氧复氧心肌细胞损伤：线粒体SIRT3信号的关键作用

目的明确内源性NAD（P）H氧化酶4（Nox4）在心肌细胞缺氧／复氧（H／R）损伤中的作用并探讨其可能的机制。方法：以H,C2心肌细胞系为研究对象,建立H／R模型,将细胞分为对照组、NC-siRNA组、Nox4-siRNA组、H／R组、H／R＋NC-siRNA组和H／R＋Nox4-siRNA组。采用RNAi方法下调Nox4的表达,MTT比色法测定相对存活率、荧光素酶化学发光法测量ATP水平,MitoSOX荧光探针检测线粒体ROS,比色法测定NAD＋／NADH的比值,Western blot法测定Nox4和SIRT3表达水平。结果：与对照组相比,H／R组H。c,心肌细胞中Nox4蛋白的水平明显增加（P〈0．05）,相对存活率、ATP的水平明显降低（P〈0．05,P〈0．01）,而线粒体ROS生成明显增加（P〈0．01）,同时NAD＋／NADH的比值明显增加、SIRT3表达量明显降低（P〈0．05,P〈0．01）。与H／R组相比,H／R＋Nox4-siRNA组Nox4蛋白水平显著降低（P〈0．05）,相对存活率、ATP的水平进一步降低、线粒体ROS生成进一步增加（P〈0．05）,同时,NAD＋／NADH的比值明显降低（P〈0．01）、SIRT3蛋白水平进一步降低（P〈0．05）。结论：下调Nox4可加重H／R诱导的心肌细胞损伤和氧化应激,抑制线粒体能量生成,其心肌细胞保护机制可能是通过上调NAD＋／NADH的比值,增加SIRT3的表达而发挥作用。     

SIRT3对SD大鼠体外循环心功能的影响

目的 探讨心肌线粒体去乙酰化酶 SIRT3对大鼠体外循环(CPB)所致急性心功能下降的影响及机制。方法 Sprague-Dawley(SD)成年大鼠30只,随机分为3组:对照组(sham组)、体外循环组(CPB组)、外源性烟酰胺腺嘌呤二核苷酸(NAD+)治疗体外循环组(NAD+治疗组),每组10只（n=10）。麻醉复苏后1 h,采用彩色多普勒超声诊断仪检测左心室收缩末期内径(LVIDs)、左心室舒张末期内径(LVIDd)、短轴缩短率(FS)及左心室射血分数(LVEF)。然后处死SD大鼠,取心肌组织,检测 AMPK、p-AMPK和心肌细胞膜Glut-4的蛋白表达及SIRT3和AMPK的活性。结果 与sham组相比,CPB组在CPB后血糖升高(P<0.05),心功能下降(P<0.05),具体表现为LVIDs和LVIDd值升高(P<0.05)、FS和LVEF值下降(P<0.05),CPB后SD大鼠心肌的SIRT3活性下降(P<0.05),下游的AMPK磷酸化水平及AMPK活性下降以及心肌细胞膜Glut-4的蛋白表达下降（均P<0.05）;预先采用外源性NAD+治疗,可显著降低血糖水平(P<0.05),提高CPB后SD大鼠心肌SIRT3的活性,促进心肌AMPK的磷酸化和该酶活性的升高(均P<0.05),并增加CPB大鼠心肌细胞膜Glut-4蛋白表达(P<0.05);与CPB组相比,NAD+治疗组心功能降低有所改善,表现为LVIDs和LVIDd值下降、FS和LVEF值升高(均P<0.05)。结论 NAD+治疗可明显改善SD大鼠CPB后的心功能,其机制可能与激活SIRT3,进而增加下游AMPK的磷酸化和该酶活性,以及增加心肌细胞膜Glut-4蛋白表达,并促进CPB术后心肌对葡萄糖的摄取和利用以及ATP的生成有关。     

大蒜素对自发性高血压大鼠肠系膜动脉平滑肌细胞钙电流的作用

目的:观察大蒜素(Gar)对自发性高血压大鼠(SHR)肠系膜动脉平滑肌细胞L-型钙电流(LCa,L)的影响。方法:利用双酶-两步法消化得到单个大鼠肠系膜动脉血管平滑肌细胞,用全细胞膜片钳记录钙电流。在细胞池中灌流含Gar的细胞外液,观察药物对LCa,L的作用和门控机制及门控动力学参数的改变。结果:1Gar对ICa,L的抑制效应呈浓度依赖性和电压依赖性特征。刺激电位0 mV时,200μmol/L Gar可使ICa,L峰值密度由(-8.4±0.4)pA/pF降低为(-6.1±0.3)pA/pF;2药物可使ICa,L半激活电压V1/2右移,半失活电压左移及失活后恢复动力学减慢等环节可减少通道的开放和重复开放,从而减少ICa,L峰值密度和窗口电流。结论:Gar可能通过减少细胞的钙电流发挥降压效应。     

Cardio-protective effects of pentraxin 3 produced from bone marrow-derived cells against ischemia/reperfusion injury

BackgroundInflammation is one of major mechanisms contributing to the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Pentraxin 3 (PTX3), produced in response to inflammatory signals, acts as a humoral arm of the innate immunity. Here we investigated the role of PTX3 produced from bone marrow-derived cells in myocardial I/R injury using PTX3-deficient (PTX3KO) mice.Methods and resultsPTX3KO mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow (BM) cells, generating four types of mice (WT^WT-BM, WT^PTX3KO-BM, PTX3KO^WT-BM and PTX3KO^PTX3KO-BM). Six weeks after BM transplantation, the myocardial I/R procedure (45 min of left descending coronary artery ligation followed by 48 h of reperfusion) was performed. Infarct size was greater in WT and PTX3KO mice with BM from PTX3KO donor (WT^PTX3KO-BM and PTX3KO^PTX3KO-BM) compared with WT and PTX3KO mice with BM from WT donor (WT^WT-BM and PTX3KO^WT-BM). Localization of PTX3 was observed in neutrophils and macrophages in WT and PTX3KO mice with BM from WT donor (WT^WT-BM and PTX3KO^WT-BM), while only in endothelial cells in WT mice with BM from PTX3KO donor (WT^PTX3KO-BM). Infiltration of neutrophils and generation of reactive oxygen species (ROS) at ischemic border zones were greater in PTX3KO mice with BM from PTX3KO donor (PTX3KO^PTX3KO-BM) than PTX3KO mice with BM from WT donor (PTX3KO^WT-BM). Plasma levels and cardiac expressions of interleukin-6 were higher in PTX3KO mice with BM from PTX3KO donor (PTX3KO^PTX3KO-BM) than PTX3KO mice with BM from WT donor (PTX3KO^WT-BM). However, no significant differences in infarct size, infiltration of neutrophils, generation of ROS and plasma and cardiac levels of interleukin-6 were observed between WT and PTX3KO mice with BM from WT donor and between WT and PTX3KO mice with BM from PTX3KO donor. These results indicated that the lack of PTX3 produced from BM-derived cells, and not from cardiac resident cells, exacerbated myocardial injury after I/R.ConclusionPTX3 produced from bone marrow-derived cells plays a crucial role in cardiac protection against myocardial I/R injury by attenuating infiltration of neutrophils, generation of ROS and inflammatory cytokine.     

Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha

OBJECTIVES: This study sought to assess the role of tumor necrosis factor-alpha (TNF-alpha) in myocardial ischemia/reperfusion (I/R) injury using TNF-alpha knockout (KO) mice. BACKGROUND: Tumor necrosis factor-alpha is thought to be involved in the pathogenesis of myocardial I/R injury by promoting leukocyte infiltration of the myocardium. However, the precise role of TNF-alpha in I/R injury is still unknown. METHODS: The hearts in TNF-alpha KO and wild-type (WT) mice were exposed by left lateral thoracotomy, and the left coronary artery was occluded for 30 min then reperfused for 120 min. RESULTS: The infarct size in TNF-alpha KO mice was significantly reduced compared with WT mice. The frequency of arrhythmia was decreased, and cardiac function during reperfusion was significantly improved in TNF-alpha KO mice compared with WT mice. The activation of nuclear factor-kappaB (NF-kappaB), the expression of chemokines and adhesion molecules and the infiltration of leukocytes were also significantly reduced in TNF-alpha KO mice, compared with WT mice. These findings provide evidence that TNF-alpha aggravates I/R injury. CONCLUSIONS: Tumor necrosis factor-alpha exacerbates myocardial I/R injury at an early stage of reperfusion by activating NF-kappaB, thereby inducing chemokines and adhesion molecules and facilitating leukocyte infiltration.     

激活乙醛脱氢酶2抑制糖尿病小鼠心肌羰基应激和缺血/再灌注损伤

目的:观察乙醛脱氢酶2(ALDH2)激动剂Alda-1对Ⅰ型糖尿病(DM)小鼠心肌缺血/再灌注(I/R)损伤的影响,探讨羰基应激在DM心脏缺血性损伤易感性增高中的作用。方法:以C57BL/6雄性小鼠为实验对象,腹腔注射链脲佐菌素(STZ)制备Ⅰ型DM小鼠模型。将正常C57BL/6小鼠(20只)和DM小鼠(20只)随机分为I/R组和I/R+Alda-1治疗组,每组10只。采用冠状动脉左前降支结扎缺血30 min再灌注4 h建立在体小鼠急性心肌I/R模型,于再灌注前5 min经静脉以2 ml/(kg·h)速度分别输注生理盐水(NS)或Alda-1(16 mg/kg)并持续到再灌注结束。再灌注结束后取血检测血清乳酸脱氢酶(LDH)水平,取心肌组织检测ALDH2活性、心肌内活性氧簇(ROS)水平,蛋白羰基化程度和心肌梗死(MI)面积。结果:检测心肌ALDH2活性显示,DM小鼠心肌ALDH2活性较对照组显著降低。与对照组相比,DM小鼠心肌I/R损伤显著加重,表现为MI面积增大,血清LDH水平显著增加(均P0.05)。再灌注期Alda-1治疗可有效提高DM小鼠I/R心肌ALDH2活性(P0.05),并显著抑制DM小鼠的上述心肌I/R损伤(均P0.05)。DM组I/R心肌中蛋白质羰基化程度和ROS生成较对照组I/R心肌显著增加(均P0.05)。Alda-1治疗可有效改善DM小鼠I/R心肌中的蛋白质羰基化和ROS水平。结论:激活心肌ALDH2可显著改善DM小鼠心肌抗I/R损伤能力,其机制可能与减轻DM小鼠在I/R过程中导致的蛋白质氧化损伤有关。     

CXCR6 deficiency ameliorated myocardial ischemia/reperfusion injury by inhibiting infiltration of monocytes and IFN-γ-dependent autophagy

Background

Emerging evidence shows that the chemokine CXCL16 plays an important role in the pathogenesis of myocardial remodeling and development of heart failure following ischemia/reperfusion (I/R) injury. CXCR6, the receptor for CXCL16, is also critically involved. However, the underlying mechanism remained uncertain, and the aim of this research was to investigate this mechanism in CXCR6 knockout (KO) mice.

Methods and results

CXCR6 KO mice and wild type (WT) mice had no overt phenotype at baseline in the absence of injury, but difference was shown in response to I/R induction. Compared with WT mice, CXCR6 KO mice exhibited a lower infarction size (31.86 ± 1.808% vs. 43.09 ± 1.519%), and better cardiac function (measured by LVEF, LVFS, + dp/dt, LVEDP, and LVSP) following I/R. Moreover, cardiac levels of IFN-γ and IFN-γ-dependent autophagy were found to be significantly attenuated in CXCR6 KO mice. Further data showed that cardiac-enhanced IFN-γ secretion was not induced by cardiomyocytes, but by infiltrated monocytes in the myocardium in response to I/R injury. In vivo injection of IFN-γ and in vitro co-cultured cardiomyocytes with CD11b + monocytes confirmed IFN-γ activated autophagic response, and induced cardiac dysfunction in a paracrine manner.

Conclusions

The study suggested that since disruption of the CXCL16/CXCR6 signaling cascade had a cardio-protective effect against I/R injury, the underlying mechanism might be that I/R triggered the infiltration of monocytes into the myocardium, and induced cardiac autophagy through CXCL16/CXCR6-dependent paracrine secretion of IFN-γ.     

Mitochondria to nucleus translocation of AIF in mice lacking Hsp70 during ischemia/reperfusion

Heat shock protein 70 (Hsp70) has been shown to have an anti-apoptotic function, but its mechanism is not clear in heart. In this study, we examined the effect of Hsp70 deletion on AIF-induced apoptosis during ischemia/reperfusion (I/R) in vivo. Although Hsp70 KO and WT mice demonstrated similar amounts of AIF released from mitochondria after I/R surgery, Hsp70 KO mice showed a significantly greater increase in apoptosis, larger infarct size, and decreased cardiac output. There was also a significant fourfold increase in the nuclear accumulation of AIF in Hsp70 KO mice compared with WT mice. Treatment with 4-AN (4-amino-1,8-napthalimide, 3 mg/kg), a potent inhibitor of PARP-1, which is a critical regulator of AIF-induced apoptosis, significantly blocked the release of AIF from mitochondria and the translocation of AIF into the nuclei after I/R in both WT and Hsp70 KO mice. In addition, 4-AN treatment resulted in a significant inhibition of apoptosis, a reduction of infarct size, and attenuated cardiac dysfunction in both WT and Hsp70 KO mice after I/R. The anti-apoptotic function of Hsp70 occurs through the inhibition of AIF-induced apoptosis by blocking the mitochondria to nucleus translocation of AIF. PARP-1 inhibition improves cardiac function by blocking AIF-induced apoptosis.