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Abstract：
BACKGROUND: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
METHODS: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined.
RESULTS: TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam).
CONCLUSIONS: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
METHODS: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined.
RESULTS: TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam).
CONCLUSIONS: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
摘要：
背景：急性心肌损伤（AMI），它是由肾缺血再灌注（IR）引起的，是急性肾损伤（AKI）相关死亡的重要原因。肥胖增加AMI和AKI的严重程度和频率。丹参酮IIA(TIIA)联合环孢素A(CsA)预处理减轻肾IR诱导的心肌细胞凋亡,并确定TIIA联合CsA是否会通过PI3K/Akt/Bad途径调节线粒体功能来减轻肥胖大鼠的心肌细胞凋亡。
方法:男性比率被喂食高脂肪饮食8周以产生肥胖。肾缺血30分钟后再灌注24小时可诱发AKI。肥胖大鼠在肾脏IR前30分钟给予TIIA（10mg/kg·d）2周和CsA（5mg/kg）。再灌注24小时后，老鼠被麻醉，血液从腹主动脉取出，肾脏从腹腔取出，然后对相关指标进行了检验。
结果：TIIA联合CsA可减轻肾IR诱导的心肌细胞病理组织学损伤和凋亡。TIIA联合CsA可改善肥胖大鼠肾缺血（30min）再灌注（24h）后的心功能。同时,TIIA联合CsA改善线粒体功能。线粒体功能异常受到呼吸控制率（RCR）降低的支持，细胞内三磷酸腺苷（ATP），耗氧率,和线粒体膜电位（MMP），线粒体活性氧（ROS）的增加，线粒体通透性转换孔（mPTP）的开放，线粒体DNA损伤，和线粒体呼吸链复合酶。线粒体动态功能的损伤是通过减少动力蛋白相关蛋白1（Drp1），和mitofusin1/2（Mfn1/2）的增加，线粒体生物发生损伤通过PPARγ共激活因子-1-α（PGC-1）的减少来评估，核呼吸因子1（Nrf1），和线粒体转录因子A(TFam)。
结论：我们从大鼠心肌组织中分离线粒体，证明心肌线粒体功能障碍与肾脏IR一起发生，从而诱导心肌细胞凋亡；肥胖加重细胞凋亡。TIIA联合CsA通过PI3K/Akt/Bad通路调节线粒体功能减轻肥胖大鼠心肌细胞凋亡。
方法:男性比率被喂食高脂肪饮食8周以产生肥胖。肾缺血30分钟后再灌注24小时可诱发AKI。肥胖大鼠在肾脏IR前30分钟给予TIIA（10mg/kg·d）2周和CsA（5mg/kg）。再灌注24小时后，老鼠被麻醉，血液从腹主动脉取出，肾脏从腹腔取出，然后对相关指标进行了检验。
结果：TIIA联合CsA可减轻肾IR诱导的心肌细胞病理组织学损伤和凋亡。TIIA联合CsA可改善肥胖大鼠肾缺血（30min）再灌注（24h）后的心功能。同时,TIIA联合CsA改善线粒体功能。线粒体功能异常受到呼吸控制率（RCR）降低的支持，细胞内三磷酸腺苷（ATP），耗氧率,和线粒体膜电位（MMP），线粒体活性氧（ROS）的增加，线粒体通透性转换孔（mPTP）的开放，线粒体DNA损伤，和线粒体呼吸链复合酶。线粒体动态功能的损伤是通过减少动力蛋白相关蛋白1（Drp1），和mitofusin1/2（Mfn1/2）的增加，线粒体生物发生损伤通过PPARγ共激活因子-1-α（PGC-1）的减少来评估，核呼吸因子1（Nrf1），和线粒体转录因子A(TFam)。
结论：我们从大鼠心肌组织中分离线粒体，证明心肌线粒体功能障碍与肾脏IR一起发生，从而诱导心肌细胞凋亡；肥胖加重细胞凋亡。TIIA联合CsA通过PI3K/Akt/Bad通路调节线粒体功能减轻肥胖大鼠心肌细胞凋亡。
