淫羊藿次苷Ⅱ通过改善内质网应激和caspase-12信号改善SHR大鼠左心室功能
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摘要
目的基于内质网应激与caspase-12信号,探索淫羊藿次苷Ⅱ(icarisideⅡ, ICSⅡ)改善自发性高血压大鼠(spontaneously hypertensive rats, SHRs)左心室功能的机制。方法 30只14周龄♂SHRs分为模型组、ICSⅡ低、中、高剂量(4、8、16 mg·kg~(-1))组及阳性药氯沙坦(20 mg·kg~(-1))组(n=6);同时,WKY作为空白对照组(n=6)。在第26周给药结束后,麻醉大鼠,用小动物超声检测大鼠左心室功能;RT-PCR检测左心室GRP78 mRNA水平;Western blot检测左心室GRP78、cleaved-caspase-12/9/3蛋白水平。结果与WKY组相比,SHR组大鼠左心室舒张末期的内径和后壁厚度增加,射血分数和短轴缩短率降低;GRP78 mRNA和蛋白水平上调,cleaved-caspase-12/9/3蛋白水平增加(P <0. 05)。与SHR组相比,ICSⅡ中、高剂量组及阳性药组左心室舒张末期的内径和后壁厚度降低(P <0. 05),射血分数和短轴缩短率增加(P <0. 05); GRP78 mRNA和蛋白水平下调,cleaved-caspase-12/9/3蛋白水平降低(P <0. 05)。结论ICSⅡ可改善SHRs左心室功能,其作用机制可能与改善内质网应激、下调升高的caspase-12信号有关。
Aim To explore the mechanism of icariside Ⅱ(ICS Ⅱ) on improving left ventricular function based on endoplasmic reticulum stress and caspase-12 signaling in spontaneously hypertensive rats(SHRs). Methods Thirty 14-week-old male SHRs were divided into model group, ICS Ⅱ low, middle and high dose groups and positive drug group(n=6). WKY was used as control group(n=6). ICS Ⅱ groups were respectively given ICS Ⅱ 4, 8, 16 mg·kg~(-1)(ig, qd), and positive drug group was given losartan(20 mg·kg~(-1)). At the end of 26 th weeks, anesthetized rats were measured by ultrasound for detection of the left ventricular function, RT-PCR was used to determine the level of GRP78 mRNA in the left ventricle tissue, and Western blot was used to assess the levels of GRP78 and cleaved-caspase-12/9/3 protein in the left ventricle tissues. Results Compared with WKY group, the internal diameter and posterior wall thickness of the left ventricular end diastolic increased, while the ejection fraction and fractional shortening decreased in SHR group. GRP78 mRNA and protein levels were up-regulated, and the levels of cleaved-caspase-12/9/3 protein were raised in left ventricle(P<0.05). Compared with SHR group, the internal diameter and posterior wall thickness of the left ventricular end diastolic increased in ICS Ⅱ medium and high dose groups and positive drug group(P<0.05), while the ejection fraction and fractional shortening decreased(P<0.05). GRP78 mRNA and protein levels were down-regulated, the levels of cleaved-caspase-12/9/3 protein declined in left ventricle(P<0.05). Conclusions ICS Ⅱ could improve left ventricular function in SHRs, and its mechanism may be related to improving left ventricular endoplasmic reticulum stress and down-regulating the elevated caspase-12 signaling.
Aim To explore the mechanism of icariside Ⅱ(ICS Ⅱ) on improving left ventricular function based on endoplasmic reticulum stress and caspase-12 signaling in spontaneously hypertensive rats(SHRs). Methods Thirty 14-week-old male SHRs were divided into model group, ICS Ⅱ low, middle and high dose groups and positive drug group(n=6). WKY was used as control group(n=6). ICS Ⅱ groups were respectively given ICS Ⅱ 4, 8, 16 mg·kg~(-1)(ig, qd), and positive drug group was given losartan(20 mg·kg~(-1)). At the end of 26 th weeks, anesthetized rats were measured by ultrasound for detection of the left ventricular function, RT-PCR was used to determine the level of GRP78 mRNA in the left ventricle tissue, and Western blot was used to assess the levels of GRP78 and cleaved-caspase-12/9/3 protein in the left ventricle tissues. Results Compared with WKY group, the internal diameter and posterior wall thickness of the left ventricular end diastolic increased, while the ejection fraction and fractional shortening decreased in SHR group. GRP78 mRNA and protein levels were up-regulated, and the levels of cleaved-caspase-12/9/3 protein were raised in left ventricle(P<0.05). Compared with SHR group, the internal diameter and posterior wall thickness of the left ventricular end diastolic increased in ICS Ⅱ medium and high dose groups and positive drug group(P<0.05), while the ejection fraction and fractional shortening decreased(P<0.05). GRP78 mRNA and protein levels were down-regulated, the levels of cleaved-caspase-12/9/3 protein declined in left ventricle(P<0.05). Conclusions ICS Ⅱ could improve left ventricular function in SHRs, and its mechanism may be related to improving left ventricular endoplasmic reticulum stress and down-regulating the elevated caspase-12 signaling.
引文
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[13] Liu Z W, Zhu H T, Chen K L, et al. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy [J]. Cardiovasc Diabetol, 2013, 12: 158.
[14] Eizirik D L, Cardozo A K, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus [J]. Endocr Rev, 2008, 29(1): 42-61.
[15] Zheng Q Y, Li P P, Jin F S, et al. Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells [J]. Cell Signal, 2013, 25(1): 206-13.
[16] Liu P F, Hu Y C, Kang B H, et al. Expression levels of cleaved caspase-3 and caspase-3 in tumorigenesis and prognosis of oral tongue squamous cell carcinoma [J]. PLoS One, 2017, 12(7): e0180620.
[2] Shekhar A, Heeger P, Reutelingsperger C, et al. Targeted imaging for cell death in cardiovascular disorders [J]. JACC Cardiovasc Imaging, 2018, 11(3): 476-93.
[3] de las Fuentes L, Herrero P, Peterson L R, et al. Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease [J]. Hypertension, 2003, 41(1): 83-7.
[4] Zhang Z, Zhao L, Zhou Y, et al. Taurine ameliorated homocysteine-induced H9C2 cardiomyocyte apoptosis by modulating endoplasmic reticulum stress [J]. Apoptosis, 2017, 22(5): 647-61.
[5] Liu M Q, Chen Z, Chen L X. Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases [J]. Acta Pharmacol Sin, 2016, 37(4):425-43.
[6] Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress [J]. J Biol Chem, 2001, 276(17): 13935-40.
[7] Zhang Q, Li H, Wang S, et al. Icariin protects rat cardiac H9c2 cells from apoptosis by inhibiting endoplasmic reticulum stress [J]. Int J Mol Sci, 2013, 14(9): 17845-60.
[8] 吴雨婷,付舒,岳云,等.淫羊藿次苷Ⅱ改善自发性高血压大鼠左心室心肌细胞凋亡[J].中国药理学通报, 2017, 33(12): 1744-9.[8] Wu Y T, Fu S, Yue Y, et al. Icariside Ⅱ improves left ventricular cardiomyocyte apoptosis in spontaneously hypertensive rats[J]. Chin Pharmacol Bull, 2017, 33(12): 1744-9.
[9] Giles T D, Berk B C, Black H R, et al. Expanding the definition and classification of hypertension [J]. J Clin Hypertens (Greenwich), 2005, 7(9): 505-12.
[10] Dai H, Zhang X, Yang Z, et al. Effects of baicalin on blood pressure and left ventricular remodeling in rats with renovascular hypertension [J]. Med Sci Monit, 2017, 23: 2939-48.
[11] Marchi S, Patergnani S, Missiroli S, et al. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death [J]. Cell Calcium, 2018, 69: 62-72.
[12] Young C N. Endoplasmic reticulum stress in the pathogenesis of hypertension [J]. Exp Physiol, 2017, 102(8): 869-84.
[13] Liu Z W, Zhu H T, Chen K L, et al. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy [J]. Cardiovasc Diabetol, 2013, 12: 158.
[14] Eizirik D L, Cardozo A K, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus [J]. Endocr Rev, 2008, 29(1): 42-61.
[15] Zheng Q Y, Li P P, Jin F S, et al. Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells [J]. Cell Signal, 2013, 25(1): 206-13.
[16] Liu P F, Hu Y C, Kang B H, et al. Expression levels of cleaved caspase-3 and caspase-3 in tumorigenesis and prognosis of oral tongue squamous cell carcinoma [J]. PLoS One, 2017, 12(7): e0180620.