SRT1720对高糖诱导的小鼠系膜细胞凋亡的影响

目的观察Sirt1激活剂SRT1720对高糖诱导的小鼠肾小球系膜细胞凋亡的作用。方法体外培养小鼠肾小球系膜细胞,随机分为正常糖组、正常糖+甘露醇组、高糖组及高糖+SRT1720组。采用原位末端转移酶标记技术(TUNEL)及流式细胞术检测细胞凋亡;流式细胞术检测活性氧簇(ROS)产生;Western blot检测caspase-3、cleaved caspase-3、Bax、Bcl-2、p38 MAPK、p-p38 MAPK、Sirt1、p53、乙酰化p53及细胞色素C的表达;实时定量PCR检测Bax和Bcl-2 mRNA的表达。结果与正常糖对照组相比,高糖组系膜细胞ROS产生和细胞凋亡明显增加,cleaved caspase-3、p-p38 MAPK和乙酰化p53表达增高、Bax/Bcl-2比率明显升高、Sirt1表达下降以及细胞色素C易位。SRT1720干预能够明显抑制高糖诱导的系膜细胞凋亡和ROS产生;下调cleaved caspase-3、乙酰化p53和p-p38 MAPK的表达;上调Sirt1的表达;减少Bax/Bcl-2比率和细胞色素C易位。结论SRT1720能够抑制高糖诱导的系膜细胞凋亡,可能是通过减少ROS产生、保护线粒体功能、抑制p53乙酰化以及p38MAPK信号通路激活而实现的。     

银杏二萜内酯葡胺注射液通过抑制p38/p53通路保护氧糖剥夺SY5Y细胞的机制

目的探讨银杏二萜内酯葡胺注射液(diterpene ginkgolides meglumine injection,DGMI)对缺糖/缺氧损伤(oxygen-glucose deprivation,OGD)的人神经母细胞瘤细胞(SY5Y)保护的作用及可能的机制。方法 SY5Y细胞OGD损伤4 h后,予药物复氧1 h,然后测定细胞存活率(CCK-8法)、凋亡坏死比率、线粒体膜电位(ΔΨm);蛋白质免疫印迹检测细胞中p-p38、p-p53、Bcl-2、Bax和cleaved caspase-9、cleaved caspase-3蛋白量的变化。结果 DGMI能明显提高OGD损伤的SY5Y细胞的存活率,降低细胞凋亡比率,挽救下降的线粒体膜电位(ΔΨm)。下调p-p38、p-p53、Bax/Bcl-2、cleaved caspase-9、cleaved caspase-3等蛋白量,抑制p38和p53活性,保护神经细胞。结论DGMI对OGD损伤的SY5Y细胞具有明显的保护作用,其保护机制可能与细胞内p38/p53/Bcl-2/caspase-9/caspase-3信号通路的抑制有关。     

N-乙酰半胱氨酸影响p38有丝分裂原活化蛋白激酶对顺铂诱导急性肾损伤的保护作用

目的研究N-乙酰半胱氨酸(N-acetylcysteine,NAC)对顺铂(cisplatin,CDDP)诱导大鼠急性肾损伤(acute kidney in-jury,AKI)后组织细胞凋亡的影响和与p38有丝分裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)的关系。方法静脉注射CDDP制备大鼠AKI模型。大鼠随机分为正常对照组、AKI模型对照组、NAC低剂量组(50 mg.kg-1)、NAC中剂量组(100 mg.kg-1)、NAC高剂量组(200 mg.kg-1)、特异性p38MAPK抑制剂SB203580组(10mg.kg-1)。大鼠预先连续给药3 d,给予CDDP,再继续给药5 d。TUNEL法进行细胞凋亡检查。试剂盒测定肾脏组织caspase-3。Western blot测定caspase-3、Bax、Bcl-2、磷酸化p38MAPK(phosphorylated p38MAPK,p-p38MAPK)表达。结果与正常对照组相比,CDDP诱导AKI模型组肾组织凋亡细胞增加,caspase-3、Bax、p-p38MAPK表达升高,Bcl-2表达降低(P<0.01)。与AKI模型组相比,NAC与SB203580减少凋亡细胞、降低肾脏组织caspase-3、Bax、p-p38MAPK表达和增加Bcl-2表达(P<0.01)。结论 NAC可有效防治CD-DP诱导大鼠AKI,并与p38MAPK相关。     

己酮可可碱联合骨髓间充质干细胞对高糖诱导的小鼠肾小球系膜细胞凋亡及氧化应激的影响

目的探讨己酮可可碱(PTX)联合骨髓间充质干细胞(MSC)对高糖诱导下小鼠肾小球系膜细胞凋亡和氧化应激的影响。方法葡萄糖30 mmol·L~(-1)刺激培养12 h的小鼠肾小球系膜细胞,肾小球系膜细胞分为细胞对照组、高糖组、高糖+MSC组(高糖系膜细胞与MSC按1∶10共培养)、高糖+MSC+PTX 0.1,0.3和1.0 mmol·L~(-1)组,孵育48 h。酶联免疫法检测系膜细胞超氧化物歧化酶(SOD)活性、丙二醛(MDA)和活性氧(ROS)含量;流式细胞术检测系膜细胞凋亡;Western印迹法检测系膜细胞中Bcl-2,Bax,胱天蛋白酶3、胱天蛋白酶8和胱天蛋白酶9蛋白表达水平。结果与细胞对照组相比,高糖组系膜细胞的SOD活性显著降低,MDA和ROS含量显著升高(P<0.01)。与高糖组相比,高糖+MSC组、高糖+MSC+PTX 0.1,0.3和1.0 mmol·L~(-1)组SOD活性显著升高,MDA和ROS含量显著降低(P<0.01)。与细胞对照组相比,高糖组细胞凋亡率显著升高(P<0.01);Bax、胱天蛋白酶3、胱天蛋白酶8和胱天蛋白酶9蛋白表达水平显著升高(P<0.01),但Bcl-2蛋白表达水平显著降低(P<0.01)。与高糖组相比,高糖+MSC组、高糖+MSC+PTX 0.1,0.3和1.0 mmol·L~(-1)组细胞凋亡率显著降低(P<0.01);Bax、胱天蛋白酶3、胱天蛋白酶8和胱天蛋白酶9蛋白表达水平显著降低(P<0.01),Bcl-2蛋白表达水平显著升高(P<0.01)。结论 PTX联合MSC可通过减少肾小球系膜细胞凋亡以及抑制其氧化应激来改善糖尿病肾病。     

氟伐他汀对高糖培养大鼠肾小球系膜细胞CTGF mRNA的影响及其作用机制的研究

目的探讨高糖状态下肾小球系膜细胞中结缔组织生长因子（CTGF）mRNA的表达以及HMG-CoA还原酶抑制剂氟伐他汀对其的影响及作用机制。方法体外培养大鼠肾小球系膜细胞,实验分为4组：低糖组（LG组,5.5 mmol/L葡萄糖）;低糖＋甘露醇组（LG＋M组,5.5 mmol/L葡萄糖＋24.5 mmol/L甘露醇）;高糖组（HG组,30 mmol/L葡萄糖）;高糖＋氟伐他汀组（HG＋Flu组,30 mmol/L葡萄糖＋10μmol/L氟伐他汀）。采用逆转录-聚合酶链反应（RT-PCR）检测CTGF和纤维粘连蛋白（FN）mRNA的表达,Western印迹检测磷酸化p38丝裂原活化蛋白激酶（p-p38 MAPK）及其下游因子cAMP反应元件结合蛋白1（p-CREB1）。结果与LG＋M组相比,HG组系膜细胞增殖明显,p-p38 MAPK、p-CREB1表达明显上调,CTGF和FN mRNA的表达增加。与HG组比较,HG＋Flu组可抑制系膜细胞增殖,p-p38 MAPK、p-CREB1的表达明显下调,CTGF和FN mRNA的表达降低。结论高糖状态下肾小球系膜细胞CTGF mRNA表达增强,p-p38 MAPK和p-CREB1表达明显升高,氟伐他汀抑制肾小球系膜细胞CTGF mRNA和细胞外基质的分泌可能部分是通过影响p38 MAPK及其下游核因子CREB1的激活而实现。     

肝X受体通过NF-κB信号通路减轻高糖诱导的H9C2细胞凋亡

目的探讨肝X受体(LXRs)是否通过抑制核转录因子κB(NF-κB)表达减轻高糖诱导的H9C2细胞凋亡。方法LXRs过表达慢病毒载体的构建及转染高糖培养的H9C2细胞;实验分组:对照组(5.5 mmol·L-1葡萄糖)、甘露醇组(5.5 mmol·L-1葡萄糖+27.5 mmol·L-1甘露醇)、高糖组(33 mmol·L-1葡萄糖)、GFP组、LXRα组、LXRβ组。检测细胞增殖抑制率,Bax mRNA、Bcl-2 mRNA表达,NF-κB、Bax、Bcl-2、Cleaved caspase-3蛋白量,细胞凋亡率。结果过表达LXRs组明显降低高糖诱导的Bax、NF-κB及Cleaved caspase-3蛋白表达及细胞凋亡(P<0.05),上调由高糖抑制Bcl-2的表达(P<0.05)。结论 LXRs通过NF-κB信号通路减轻高糖诱导的H9C2细胞凋亡。     

吡格列酮对肾小球系膜细胞ROS和p38MAPK的影响

目的观察吡格列酮(PIO)对高糖培养的肾小球系膜细胞(MCs)p38丝裂原活化蛋白激酶(p38MAPK)表达和活性氧(ROS)水平的影响,探讨PIO肾保护作用及机制。方法体外培养MCs,随机分为正常对照组(NG组)、高糖(HG组)及高糖+不同浓度吡格列酮组。应用流式细胞术检测细胞ROS水平,半定量RT-PCR测定MCs p38MAPK mRNA表达情况。结果与NG组比较,HG组细胞内ROS水平明显增加,p38MAPK mRNA表达增多(P<0.01);各PIO干预组上述变化明显受抑制(P<0.01或P<0.05),且呈剂量依赖性。结论吡格列酮可拮抗高糖诱导的MCs内ROS和p38MAPK高表达。     

雷公藤甲素诱导人肝细胞凋亡的机制

目的 探讨雷公藤甲素诱导人肝细胞L-02凋亡的机制.方法 将L-02细胞分为对照组和雷公藤甲素50 nM实验组,处理48 h后,采用MTT法检测细胞存活率,流式细胞术检测细胞凋亡率、活性氧(ROS)的荧光强度,试剂盒检测细胞色素C的浓度以及半胱天冬氨酸蛋白酶9(Caspase-9)和Caspase-3的活性,Western blot检测细胞中B细胞淋巴瘤-白血病2(Bcl-2)和Bcl相关X蛋白(Bax)的表达.结果 与对照组相比,实验组细胞存活率下降,细胞凋亡率上升,Bcl-2表达下调,Bax表达、细胞色素C浓度、ROS荧光强度、Caspase-9和Caspase-3活性均明显上调(P＜0.05或P＜0.01).结论 雷公藤甲素可以抑制L-02细胞的存活,通过激活线粒体凋亡途径促进L-02细胞凋亡,下调Bcl-2与Bax比率,促进细胞色素C释放,诱导ROS生成,进一步破坏线粒体膜,增加细胞色素C的释放,激活Caspase-9和Caspase-3介导的细胞凋亡通路,最终诱导细胞凋亡.     

迷迭香酸衍生物RAD-9通过PI3K/Akt和p38 MAPK信号通路诱导胃癌MGC-803细胞凋亡

目的研究迷迭香酸衍生物RAD-9诱导胃癌MGC-803细胞凋亡的作用及其机制。方法 MTT法观察RAD-9对胃癌MGC-803细胞增殖的抑制作用;流式细胞术检测细胞的凋亡;Hoechst 33258染色法观察RAD-9对MGC-803细胞核凋亡形态学的影响;Western blot检测RAD-9干预MGC-803细胞36 h后,对Akt、p-Akt、p38 MAPK、p-p38 MAPK蛋白及凋亡相关蛋白Bcl-2、Bax、caspase-3的影响。结果MTT结果显示,RAD-9呈时间、浓度依赖性抑制胃癌MGC-803细胞增殖;流式细胞术结果显示,RAD-9对胃癌MGC-803细胞有明显的促凋亡作用(P<0.01);Hoechst 33258染色实验结果显示,RAD-9干预胃癌MGC-803细胞36 h后,细胞核呈现典型凋亡形态学改变;Western blot结果显示,RAD-9干预胃癌MGC-803细胞36 h后,Bcl-2蛋白表达水平明显降低,Bax、caspase-3蛋白表达水平明显提高,Akt、p-Akt蛋白表达水平明显下调,p38 MAPK、p-p38 MAPK蛋白表达水平明显上调(P<0.01)。结论 RAD-9能抑制胃癌MGC-803细胞生长,且能诱导其凋亡,其机制可能与抑制PI3K/Akt和激活p38 MAPK信号通路相关。     

大黄素对高糖培养的GMC增殖、FN表达及p38MAPK的影响

目的本研究旨在观察大黄素对高糖培养的大鼠肾小球系膜细胞(GMC)的增殖与细胞外基质的主要成分——纤维连接蛋白(FN)表达的影响,观察大黄素对高糖培养的p38MAPK信号转导通路的影响,以探讨大黄素调节p38MAPK信号通路抗糖尿病肾脏纤维化的分子作用机制。方法 MTT比色法检测细胞活力;流式细胞仪检测细胞周期分布;Western blot方法检测FN、p-p38MAPK蛋白表达情况。结果高糖能够诱导大鼠GMC增殖、上调FN的表达以及促进p38MAPK活化,与正常培养组相比差异有统计学意义(P<0.05);大黄素可以抑制高糖诱导的大鼠GMC增殖、FN表达与p38MAPK活化,与高糖组相比差异有统计学意义(P<0.05)。结论大黄素抗糖尿病肾脏纤维化的作用可能与大黄素抑制p38MAPK信号通路密切相关。     

Schizandrin prevents damage of murine mesangial cells via blocking NADPH oxidase-induced ROS signaling in high glucose

High glucose (HG) is the underlying factor contributing to long term complication of diabetes mellitus. Reactive oxygen species (ROS) have been postulated as a unifying mechanism for HG-induced complications. NADPH oxidase, producing superoxide anion, is the main source of ROS in diabetic nephropathy. In this study we report the inhibitory effect of schizandrin (Sch), an active ingredient of Fructus schisandrae, on HG-induced murine mesangial cells (MMCs) damage. Sch treatment significantly attenuated HG-induced proliferation and protein synthesis of MMCs in a dose dependent manner. The intracellular reactive oxygen species (ROS) level was also remarkably reduced by Sch as well as the enhanced NADPH oxidase activity, superoxide anion levels, NOX4 and p22phox protein expression, and phosphorylation of p47phox and p67phox. The phosphorylation level of mitogen activated kinase (MAPK) protein, phospho-Erk1/2 and -p38, and Akt was also significantly inhibited by Sch under HG condition. By using specific inhibitors, we found that Sch inhibits HG-induced mesangial cell proliferation and ECM overexpression via NADPH oxidase/PI3K–Akt–MAPK-dependent pathway in MMCs. Taken together; our demonstration of the ability of Sch to inhibit high glucose induced damage of MMCs has clinical implications in treatment of diabetic nephropathy.     

Cadmium induces apoptotic cell death in WI 38 cells via caspase-dependent Bid cleavage and calpain-mediated mitochondrial Bax cleavage by Bcl-2-independent pathway

Previous reports have demonstrated that cadmium (Cd) may induce cell death via apoptosis, but the mechanism responsible for cellular death is not clear. In this study, we investigated the signaling pathways implicated in Cd-induced apoptosis in lung epithelial fibroblast (WI 38) cells. Apoptotic features were observed using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, propidium iodide staining and DNA laddering. A treatment of cadmium caused the caspase-8-dependent Bid cleavage, the release of cytochrome c (Cyt c), activation of caspase-9 and -3, and PARP cleavage. A caspase-8 specific inhibitor prevented the Bid cleavage, caspase-3 activation and cell death. Alternatively, we observed that full-length Bax was cleaved into 18-kDa fragment (p18/Bax); this was initiated after 12 h and by 36 h the full-length Bax protein was totally cleaved to the p18/Bax, which caused a drastic release of Cyt c from mitochondria. The p18/Bax was detected exclusively in the mitochondrial fraction, and it originated from mitochondrial full-length Bax, but not from the cytosol full-length Bax. Cd also induced the activation of the mitochondrial 30-kDa small subunit of calpain that was preceded by Bax cleavage. Cd induced the upregulation of Bcl-2 and the degradation of p53 protein. N-acetyl cysteine effectively inhibited the Cd-induced DeltaPsim reduction, indicating ROS acts upstream of mitochondrial membrane depolarization. Taken together, our results suggest that Cd-induced apoptosis was thought to be mediated at least two pathways; caspase-dependent Bid cleavage, and the other is calpain-mediated mitochondrial Bax cleavage. Moreover, we found that the function of Bid and Bax was not dependent of Bcl-2, and that ROS can also contribute in the Cd-induced cell death.     

Arachidonic acid-induced apoptosis of human neuroblastoma SK-N-SH cells is mediated through mitochondrial alteration elicited by ROS and Ca-evoked activation of p38α MAPK and JNK1

Arachidonic acid (AA)-induced apoptosis of human neuroblastoma SK-N-SH cells was characteristic of elevation of intracellular Ca²⁺ concentration ([Ca²⁺]i), ROS generation, activation of 38 MAPK and JNK and loss of mitochondrial membrane potential (ΔΨm). Subsequent modulation of Bcl-2 family members and cytochrome c release accompanied with activation of caspase-9 and -3 were involved in the death of SK-N-SH cells. BAPTA-AM (Ca²⁺ chelator) pretreatment rescued viability of AA-treated cells through abolishing phosphorylation of p38 MAPK and JNK, ΔΨm loss and ROS generation. N-Acetylcysteine (ROS scavenger) pretreatment reduced the dissipation of ΔΨm, but insignificantly affected AA-induced p38 MAPK and JNK activation. SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor) attenuated mitochondrial depolarization, degradation of Bcl-2/Bcl-xL, and mitochondrial translocation of Bax. Transfection of specific siRNA proved that p38α MAPK and JNK1 were involved in modulating Bcl-2 family proteins. Taken together, our data suggest that the cytotoxicity of AA toward SK-N-SH cells is mediated through mitochondria-dependent death pathway, eliciting by AA-induced ROS generation and Ca²⁺-evoked activation of p38α MAPK and JNK1.     

The protective effect of Alpha lipoic acid on Schwann cells exposed to constant or intermittent high glucose

Diabetic peripheral neuropathy (DPN) is one of the most common and costly microvascular complications of diabetes, and no effective therapy exists. Previous studies have demonstrated that oxidative stress may be the unifying factor for the damaging effect of hyperglycemia. The aim of this study was to examine the impact of treatment with Alpha lipoic acid (ALA) on the intermittent high glucose (IHG) or high glucose (HG)-induced oxidative stress-induced mitochondrial pathway activation and Schwann cells (SCs) apoptosis in vitro. Our results suggested that IHG and HG induced SCs apoptosis in both caspase-dependent and caspase-independent pathways related to oxidative stress. More importantly, the cytotoxic effect of IHG was significantly more potent than that of HG. Treatment with ALA inhibited the IHG and HG-induced oxidative stress and apoptosis in SCs. Furthermore, treatment with ALA down-regulated the Bax expression and the release of cytochrome c and AIF translocation, but up-regulated the Bcl-2 expression in SCs. Treatment with ALA attenuated the activation of caspase-3 and caspase-9 and minimized the cleavage of PARP in SCs. These findings suggest that variability in glycemic control could be more deleterious than a constant HG and ALA antagonized the IHG-induced oxidative stress, activation of mitochondrial pathway and apoptosis in SCs.     

感染Ad-HGF对高糖诱导的人脐静脉内皮细胞Bax和Bcl-2蛋白表达的影响

目的 探讨高糖条件下感染携带肝细胞生长因子的重组腺病毒(Ad-HGF)对人脐静脉内皮细胞(humanumbilical vein endothelial cells,HUVECs)凋亡相关蛋白Bax、Bcl-2表达的影响.方法 将HUVECs分为低糖组(LG组,5.5 mmol/L)、高糖组(HG组,35 mmol/L)、腺病毒对照组(HG+ Ad-GFP组)和实验组(HG+ Ad-HGF组).检测4组HUVECs增殖情况、细胞内活性氧(ROS)水平及凋亡相关蛋白Bax、Bcl-2的表达.结果 HG组、HG+ Ad-GFP组HUVECs存活率低于LG组,HG+ Ad-HGF组高于HG组(P＜0.05,P＜0.01).HG组、HG+ Ad-HGF组HUVECs内ROS水平高于LG组,但HG+ Ad-HGF组低于HG组(P＜0.05).HG组、HG+ Ad-GFP组Bax、Bax/Bcl-2高于LG组,Bcl-2低于LG组,但HG+ Ad-HGF组Bax、Bax/Bcl-2低于HG组,Bcl-2高于HG组(P＜0.05).结论 感染Ad-HGF可通过降低细胞内ROS水平和Bax/Bcl-2减少细胞凋亡,进而对高糖诱导的HUVECs起到保护作用.     

MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells

Isoorientin (ISO) (CAS RN: 4261-42-1) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum. ISO is able to induce apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cells, however, the effects of ISO on MAPK signaling pathways remain unknown. The present study investigated the effects of ISO on this pathway, and the roles of MAPK kinases on mitochondrial-mediated apoptosis in HepG2 cells. The results showed that ISO induced cell death in a dose- and time-dependent manner, and induction apoptosis is main cause for ISO-induced cytotoxicity in HepG2 cells. ISO significantly inhibited the levels of ERK1/2 kinase and increased the expression of JNK and p38 kinases. Furthermore, U0126 (an ERK1/2 inhibitor) significantly enhanced the ISO-induced the Bax/Bcl-2 ratio, the release of cytochrome c to the cytosol fraction, and the levels of cleaved caspase-3. While SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) markedly prevented the expression of these proteins induced by ISO. Furthermore, the ROS inhibitor (NAC) notably promoted the inhibited effect of ISO on the ERK1/2 kinase. NAC also suppressed the p-JNK and p-p38, but failed to reverse the effects of ISO. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells through inactivating ERK1/2 kinase and activating JNK and p38 kinases, and ROS stimulated by ISO is able to activate the MAPK singaling pathway as the upstream signaling molecules. Initiating event of the mitochondrial-mediated apoptosis induced by ISO is MAPK signals.     

Involvement of the calcium-sensing receptor in cyclosporin A-induced cardiomyocyte apoptosis in rats

In this study, we sought to determine whether the calcium-sensing receptor (CaSR) is involved in Cyclosporin A (CsA)-induced cardiomyocyte apoptosis and identify its signal transduction pathway. Forty Wistar rats were randomly divided into four groups: the control group, the CsA group (CsA 15 mg/kg/day intraperitoneally, i.p.), the GdCl3 group (GdCI3 10 mg/kg, every other day, i.p.), and the CsA + GdCl3 group (CsA 15 mg/kg/day, i.p. and GdCl3 10 mg/kg, every other day, i.p.). The groups were treated for two weeks. Cardiomyocyte apoptosis and injury were observed by light microscopy, electron microscopy and TUNEL staining. CaSR mRNA expression was determined by RT-PCR, and CaSR protein expression was detected by western blot and immunohistochemistry. The protein expression levels of cytochrome c, cleaved caspase-9, cleaved caspase-3, Bax, and Bcl-2 were detected by western blot and immunohistochemistry. CsA increased the expression of CaSR mRNA and protein and enhanced cardiomyocyte apoptosis. GdCl3, a specific activator of CaSR, further enhanced CaSR expression and cardiomyocyte apoptosis and led to the upregulation of cytochrome c, cleaved caspase-9, cleaved caspase-3, and Bax, as well as the downregulation of Bcl-2. The present in vivo study provides further information on CsA-induced cardiomyocyte apoptosis. We determined for the first time that CaSR is involved in CsA-induced cardiomyocyte apoptosis in the rat through the activation of downstream cytochrome c-caspase-3 pathways. Furthermore, we offer evidence that the Bcl-2 family is involved in this process. These findings could provide novel strategies for the prevention and cure of CsA-induced cardiotoxicity.