CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin

Abstract

Abstract: AIM: To investigate the CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin and compare the effect of CPU86017 (racemate) with its 4 enantiomers:(7S, 13R), (7S, 13S), (7R, 13S), and (7R, 13R)-CPU86017 in this model. METHODS: The animals were randomly divided into 7 groups.The rat hypertrophied model was produced by treatment with L-thyroxin 0.2 mg·kg ^-1 ·d ^-1, sc for 10 d and treated with CPU86017 or its enantiomers 4 mg·kg ^-1 ·d ^-1, sc from d 6 to d 10.The changes in left ventricular (LV) weight index, redox system, and the NO and iNOS activity in the myocardium were investigated.The expression of mRNA of calcineurin 、NF-κB in the left ventricle was measured.RESULTS: There were significant cardiac hypertrophy and oxidative stress in rats treated by L-thyroxin.The expression of calcineurin, NFκB mRNA were upregulated (P <0.05, compared with that of control).After treatment with CPU86017 (racemate and enantiomers), LV remodeling and the redox system were improved.CPU86017 and (7S, 13R)-CPU86017 showed a better improvement on LV remodeling and the redox than the other isomers and restored the normal expression of calcineurin, NF-κB (P <0.05, P <0.01), respectively.CONCLUSION: It suggested that an up-regulation of calcineurin and NFκB possibly related to the altered intracellular calcium handling system plays a role in the progression of L-thyroxin induced cardiomyopathy and CPU-86017 and its 7S, 13R-CPU86017 enantiomer effectively inhibit the abnormal expression of calcineurin and NFκB genes, the NOS enzyme and oxidant stress in the cardiomyopathy.

Key words: CPU86017, enantiomers, L-thyroxin, cardiac hypertrophy, calcineurin

CLC Number:

QI Min-you, XIA Hui-jing, DAI De-zai, TANG Xiao-yun, SU Wei, ZHANG Can. CPU86017 and its enantiomers inhibit abnormal gene expression of calcineurin and NFκB in rat cardiomyopathy induced by L-thyroxin[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2006, 11(4): 392-397.

References

1 Ho KK, Pinsky JL, Kannel WB, Levy D.The epidemiology of heart failure:the Framingham study[J].J Am Coll Cardiol, 1993;22:6-13
2 Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D' Agostino RB, Kannel WB, et al.Lifetime risk for developing congestive heart failure:the Framingham Heart Study [J].Circulation, 2002;106:3068-72
3 Dai DZ, Hu HJ, Yang DM, Hao XM, Zhang GQ, Zhou PA, et al.Chronic levothyroxin treatment is associated with ion channel abnormalities in cardiac and neuronal cells[J].Clin Exp Pharmacol Physiol, 1999;26:819-21
4 Dai DZ, Wang HL, Zhang GQ, He GX, Chen L.Matrix is the site of indirect effects of propranolol on the ion channelopathies in cardiac remodeling by L-thyroxine[J].J Card Surg, 2002; 17:439-46
5 Bianchi G, Solaroli E, Zaccheroni V, Grossi G, Bargossi AM, Melchionda N, et al.Oxidative stress and anti-oxidant metabolites in patients with hyperthyroidism:effect of treatment[J]. Horm Metab Res, 1999;31:620-4
6 Yu F, Dai DZ, An LF, Guo XF.Heart hypertrophy induced by levothyroxine aggravates ischemic lesion and reperfusion arrhythmias in rats[J].Acta Pharmacol Sin, 1997;18:71-4
7 Wang YQ, Shi YP, Dai DZ.The therapeutic effects of CPU86017 on acute and chronic congestive cardiac failure mediated by reducing ET-1, NOS and oxidative stress in rats[J]. Drug Dev Res, 2004;63:22-32
8 Dai DZ.Multiple blockade on ion channels by CPU-86017 assessed as a new anti-arrhythmic agent[J].Acta Pharmacol Sin, 1998;19:195-6 (s53)
9 Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, et al.A calcineurin-dependent transcriptional pathway for cardiac hypertrophy [J].Cell, 1998;93:215-28
10 Purcell NH, Molkentin JD.Is nuclear factor kappaB an attractive therapeutic target for treating cardiac hypertrophy[J] ? Circulation, 2003;108:638-4
11 Wang YQ, Meng Y, Dai DZ.Influence of CPU86017and its optical isomers on blood pressure and arrhythmias induced by ischemia/reperfusion by intravenous administration in rats[J].Chinese journal of practical medicine Zhonghua Shiyong Yiyao Zazhi, 2005;6:484-5
12 Dai DZ, He YJ, Huang FH, Zhu Y, Khan HH.Comparison of inhibitory activity of berberine derivative CPU86017 and berberine on vascular contractions[J].J Chin Pharmaceut Univ, 2000;31:447-50
13 Kadenbach B.Intrinsic and extrinsic uncoupling of oxidative phosphorylation[J].Biochimica Biophys Acta, 2003;1604:77-94
14 Hao JM, Dai DZ, Yu F.The oxidative stress enhancing effects by L-thyroxin and the antioxidant effects of CPU86017, a derivative of tetrahydroberberine[J].Prog Pharm Sci, 2005;299: 417-21
15 Duntas LH.Thy roid disease and lipids[J].Thyroid, 2002;12: 287-93
16 Chen DD, Dai DZ, Lu J, Zhang XK.Propranolol and bepridil attenuating levothyroxine-induced rat cardiac hypertrophy and mitochondrial Ca²⁺-Mg²⁺-ATPase activity elevation[J].Acta Pharmacol Sin, 1996;17:516-8
17 Dai DZ, Hu HJ, Zhao J, Hao XM, Yang DM, Zhou PA, et al.Blockade of L-type calcium channel in myocardium and calcium-induced contractions of vascular smooth muscle by CPU86017[J].Acta Pharmacol Sin, 2004;25:416-23
18 Berridge MJ, Bootman MD, Lipp P.Calcium:a life and death signal[J].Nature, 1998;395:645-8
19 Crabtree GR.Generic signals and specific outcomes:signaling through Ca²⁺, calcineurin, and NF-AT[J].Cell, 1999;96:611-4
20 Hirotani S, Otsu K, Nishida K, Higuchi Y, Morita T, Nakayama H, et al.Involvement of nuclear factor-kappaB and apoptosis signal regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy[J].Circulation, 2002; 105:509-15
21 Gupta S, Purcell NH, Lin A, Sen S.Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy [J].J Cell Biol, 2002;159:1019-28

[1]	XIE Mengdie, WANG Chenchen, LI Bingtao, OUYANG Changsheng, QIU Yumei, LI Hongming, TU Jun, SHANG Guangbin, TANG Xilan. Analysis on mechanism of frankincense volatile oil in prevention and treatment of cardiac hypertrophy based on in vitro cell experiment and network pharmacology [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(3): 241-252.
[2]	ZHENG Sanfu, GUO Weixi, LUO Jinzhong, QIN Shuiqing. Role and mechanism of platelet-derived growth factor/AKT pathway in pressure overload-induced ventricular remodeling [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(2): 167-173.
[3]	WANG Zheng, WANG Hegui. Research progress of A-kinase-anchoring protein mediated regulation of cardiac hypertrophy [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(11): 1304-1308.
[4]	TAO Shao-Neng, WANG Ying-Ying, ZHOU Jian-Guo, CHENG Guang-Hua, ZHANG Meng-Ying, ZHONG Min, 吕Kun . Inhibition effects of methotrexate enantiomers on the growth of human lung cancer A549 cells [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(6): 625-630.
[5]	WANG Jiang-lin, ZUO Xiao-cong, YANG Meng, ZHOU Ling-yun. Advances in the study of post-transplantation diabetes mellitus resulting from tacrolimus via calcineurin/NFAT signaling [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(1): 74-81.
[6]	ZHOU Si-gui, XU Li-peng, LU Yao, YUAN Xi, PAN Xue-diao, ZANG Lin-quan. Fenofibrate inhibits cardiac hypertrophy by up-regulation of short-chain acyl-CoA dehydrogenase [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(8): 868-873.
[7]	YU Juan, ZHOU Yu, ZHENG Xiang, CHEN Chong-hong. Apoptosis of the neurocytes after cerebral ischemia-reperfusion injury and effects of melatonin [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(7): 740-743.
[8]	DENG Jiang, HUANG Xie-nan. Anti-cardiac hypertrophic effect of ginsenoside Rg₁ [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(3): 271-275.
[9]	LIU Xiao-ying, YANG Min, LIN Qiu-xiong, YU Xi-yong, SHAN Zhi-xin, ZHENG Meng, LIN Shuguang. Anti-apoptotic effects of carvedilol enantiomers in cardiac myocytes [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2006, 11(9): 1035-1038.
[10]	DONG Qi, CHEN Min-sheng, HUANG Shao-hua, LI Xiao-yun, LI Ying-hui, ZHANG Shu, LIU Zhen-xiu. Effects of Ca²⁺ CaM-dependent calcineurin signaling pathway on cardiomyocytes hypertrophy of rats induced by neuropeptide Y [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(1): 65-68.
[11]	ZHANG Jie, LIU Chang-Hui, HE Yong, WEI Chun-Yang, WANG Shao-Hua. Effects of valsartan on phosphatase and tensin homologue deleted on chromosome ten (PTEN) in spontaneously hypertensive rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(9): 988-991.
[12]	YAN Ling, WANG Jin-Ming, WANG Fang, LIANG Yuan-Hong, XIA Fang, SONG Xiao-Hua. Effects of β₁-adrenergic receptor mRNA antisense oligodeoxynucleotide on the hemodynamics and cardiac hypertrophy in renal hypertensive rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(9): 997-1001.
[13]	ZHANG Cheng, YE Ping, ZHANG Jie. Effects of pioglitazone on expression of myocardial proinflammatory cytokine in left ventricular hypertrophic rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(6): 658-661.
[14]	LIU Qing, DAI De-Zai. Influence of a new endothelin receptor antagonist CPU-0213 on expression of MMPs mRNA and TIMPs mRNA in rats with hypertrophic myocardium induced by L-thyroxin [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(3): 281-284.
[15]	DUAN Xiao-Chun, WANG Jin-Ming, WANG Fang, LI Heng, QIN Jin-Mei. Effects of valsartan and spironolactone on insulin-like growth factor-1 in cardiacmyocytes of spontaneously hypertensive rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(10): 1137-1141.