Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, China.
Department of Nephrology, The fourth of Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (Shenzhen Traditional Chinese Medicine Hospital), Guangzhou University of Traditional Chinese Medicine, Shenzhen, China.
BMC Complement Med Ther. 2021 Mar 22;21(1):100. doi: 10.1186/s12906-021-03270-w.
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.
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.
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).
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.
肾缺血再灌注（IR）引起的急性心肌损伤（AMI）是导致急性肾损伤（AKI）相关死亡的重要原因。肥胖会加重 AMI 和 AKI 的严重程度和频率。丹参酮 IIA（TIIA）联合环孢素 A（CsA）预处理可减轻肾 IR 诱导的心肌细胞凋亡，并通过 PI3K/Akt/Bad 通路调节线粒体功能来确定 TIIA 联合 CsA 是否会减轻肥胖大鼠的心肌细胞凋亡。
雄性大鼠喂食高脂肪饮食 8 周以产生肥胖。通过 30 分钟的肾缺血和 24 小时的再灌注来诱导 AKI。肥胖大鼠给予 TIIA（10mg/kg·d）2 周，并在肾 IR 前 30 分钟给予 CsA（5mg/kg）。再灌注 24 小时后，麻醉大鼠，从腹主动脉取血，从腹腔取肾，然后检查相关指标。
TIIA 联合 CsA 可减轻肾 IR 诱导的心肌细胞的病理损伤和凋亡。TIIA 联合 CsA 改善了肥胖大鼠肾缺血（30 分钟）-再灌注（24 小时）后的心脏功能。同时，TIIA 联合 CsA 改善了线粒体功能。线粒体功能异常表现为呼吸控制率（RCR）、细胞内三磷酸腺苷（ATP）、耗氧量和线粒体膜电位（MMP）降低，线粒体活性氧（ROS）、线粒体通透性转换孔（mPTP）开放、线粒体 DNA 损伤和线粒体呼吸链复合酶增加。通过降低与动力相关蛋白 1（Drp1）和增加线粒体融合蛋白 1/2（Mfn1/2）来评估线粒体动态功能的损伤，并通过降低过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1）、核呼吸因子 1（Nrf1）和线粒体转录因子 A（TFam）来评估线粒体生物发生损伤。
我们使用大鼠心肌组织分离的线粒体证明，心肌线粒体功能障碍伴随着肾 IR 发生，导致心肌细胞凋亡；肥胖加重了细胞凋亡。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。
