Different Proarrhythmic Effects of Aconitine on Healthy and Long QT Syndrome Patients with Human Pluripotent Stem Cell-Derived Cardiomyocytes
A B S T R A C T
Aconitine is the main toxic component in aconite, a traditional Chinese medicine, which was widely used in emergency medicine. Aconitine is highly toxic, and a single dose of 0.2mg can cause malignant arrhythmias\death in adults. Early studies have shown that aconitine can improve arrhythmia in patients by affecting the calcium channel. The dual nature of aconitine therapy and toxicity is puzzling. While cardiac Ca2+ channel opening during repolarization has long been documented in normal human cardiac myocytes, the cellular effects and mechanism of ACO in Long QT syndrome patient remains unexplored. This study aimed to assess the proarrhythmic effects of ACO in healthy and Long QT syndrome patients with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). ACO concentration-dependently (0.05 ~ 5.0 μM) decreased amplitude, which has no significant effect on cell index of normal hiPSC-CMs. While ACO 5.0 μM decreased cell index between 5-30min for Long QT syndrome hiPSC-CMs. Meanwhile, ACO had no significant effect on the amplitude and frequency of calcium transients in normal cardiomyocytes, but it significantly increased the frequency of calcium transients in special cardiomyocytes of LQT disease at 5 μM. Meanwhile, 0.05- 5 μM ACO significantly shortened the action potential duration of human cardiomyocytes in both normal and LQT groups. Effect of ACO on L-type calcium current was detected in both normal hiPSC-CMs and LQTs hiPSC-CMs; it showed a similar blockage, which suggested that L-type calcium current may not be the major target on the effect of ACO on LQT disease. In conclusion, our data suggest that ACO had different effect on human cardiomyocytes in normal and LQT (hiPSC-CMs).
Keywords
Long QT syndrome, aconitine, hiPSC-CMs
Get access to the full version of this article.
Article Info
Article Type
Research ArticlePublication history
Received:
Accepted:
Published:
Copyright
© 2023 Yue Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.JSO.2021.02.03
Author Info
Yang Liang
Xieguanghui
Wang Zihan
Huangguangyao
Zheng Bin
Zhu Jin Miao
Hong Qian
Yue Gao
Corresponding Author
Yue GaoBeijing Institution of Radiation Medicine, Beijing, China
Get access to the full version of this article.
1.
Sia D, Villanueva
A, Friedman SL, Llovet JM (2017) Liver Cancer Cell of Origin, Molecular Class,
and Effects on Patient Prognosis. Gastroenterology 152: 745-761. [Crossref]
2.
Chen W, Zheng R,
Baade PD, Zhang S, Zeng H et al. (2016) Cancer statistics in China, 2015. Ca
Cancer J Clin 66: 115-132. [Crossref]
3.
Yeh MM (2010)
Pathology of combined hepatocellular-cholangiocarcinoma. J Gastroenterol
Hepatol 25: 1485-1492. [Crossref]
4.
Sun T, Liu H,
Ming L (2017) Multiple Roles of Autophagy in the Sorafenib Resistance of
Hepatocellular Carcinoma. Cell Physiol Biochem 44: 716-727. [Crossref]
5.
Bruix J, Qin S,
Merle P, Granito A, Huang YH et al. (2017) Regorafenib for patients with
hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389:
56-66. [Crossref]
6.
Kim K, Jha R,
Prins PA, Wang H, Chacha M et al. (2017) Regorafenib in advanced hepatocellular
carcinoma (HCC): considerations for treatment. Cancer Chemother Pharmacol
80: 945-954. [Crossref]
7.
Tsuchiya N,
Sawada Y, Endo I, Saito K, Uemura Y et al. (2015) Biomarkers for the early
diagnosis of hepatocellular carcinoma. World J Gastroenterol 21: 10573-
10583. [Crossref]
8.
Zhang H, Ren L,
Ding Y, Li F, Chen X et al. (2019) Hyaluronan-mediated motility receptor
confers resistance to chemotherapy via TGFbeta/Smad2-induced
epithelial-mesenchymal transition in gastric cancer. FASEB J 33:
6365-6377. [Crossref]
9.
Bahrami SB, Tolg
C, Peart T, Symonette C, Veiseh M et al. (2017) Receptor for hyaluronan
mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous
adipogenesis. Integr Biol (Camb) 9: 223-237. [Crossref]
10. Mele V, Sokol L, Kolzer VH, Pfaff D, Muraro MG et al.
(2017) The hyaluronan-mediated motility receptor RHAMM promotes growth,
invasiveness and dissemination of colorectal cancer. Oncotarget 8:
70617-70629. [Crossref]
11. Leng Y, Abdullah A, Wendt MK, Calve S (2019)
Hyaluronic acid, CD44 and RHAMM regulate myoblast behavior during
embryogenesis. Matrix Biol 78-79: 236-254. [Crossref]
12. Yang D, Ma Y, Zhao P, Ma J, He C (2019) Systematic
screening of protein-coding gene expression identified HMMR as a potential
independent indicator of unfavorable survival in patients with papillary
muscle-invasive bladder cancer. Biomed Pharmacother 120: 109433. [Crossref]
13. Xu J, Zhang Y, Xu J, Wang M, Liu G et al. (2019)
Reversing tumor stemness via orally targeted nanoparticles achieves efficient
colon cancer treatment. Biomaterials 216: 119247. [Crossref]
14. Stone R 2nd, Sabichi AL, Gill J, Lee IL, Adegboyega P
et al. (2010) Identification of genes correlated with early-stage bladder
cancer progression. Cancer Prev Res (Phila) 3: 776-786. [Crossref]
15. Fusco N, Lopez G, Corti C, Pesenti C, Colapietro P et
al. (2018) Mismatch Repair Protein Loss as a Prognostic and Predictive
Biomarker in Breast Cancers Regardless of Microsatellite Instability. JNCI
Cancer Spectr 2: pky056. [Crossref]
16. Bidadi B, Liu D, Kalari KR, Rubner M, Hein A et al.
(2018) Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs
in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer
Patients. Front Pharmacol 9: 158. [Crossref]
17. Hauser Kawaguchi A, Tolg C, Peart T, Milne M, Turley
EA et al. (2018) A truncated RHAMM protein for discovering novel therapeutic
peptides. Bioorg Med Chem 26: 5194-5203. [Crossref]
18. Yang C, Li C, Zhang P, Wu W, Jiang X (2017) Redox
Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive
Cancer, both Primary and Metastatic Tumors. Theranostics 7: 1719-1734. [Crossref]
19. Pu S, Ren L, Liu Q, Kuang J, Shen J et al. (2016) Loss
of 5-lipoxygenase activity protects mice against paracetamol-induced liver
toxicity. Br J Pharmacol 173: 66-76. [Crossref]
20. Yao L, Cui X, Chen Q, Yang X, Fang F et al. (2017)
Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat. Cell
Rep 20: 641-654. [Crossref]
21. Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S et
al. (2007) Genome-wide molecular profiles of HCV-induced dysplasia and
hepatocellular carcinoma. Hepatology 45: 938-947. [Crossref]
22. Roessler S, Jia HL, Budhu A, Forgues M, Ye QH et al.
(2010) A unique metastasis gene signature enables prediction of tumor relapse
in early-stage hepatocellular carcinoma patients. Cancer Res 70:
10202-10212. [Crossref]
23. Chen X, Cheung ST, So S, Fan ST, Barry C et al. (2002)
Gene expression patterns in human liver cancers. Mol Biol Cell 13:
1929-1939. [Crossref]
24. Camp RL, Dolled Filhart M, Rimm DL (2004) X-tile: a new
bio-informatics tool for biomarker assessment and outcome-based cut-point
optimization. Clin Cancer Res 10: 7252-7259. [Crossref]
25. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a
Bioconductor package for differential expression analysis of digital gene
expression data. Bioinformatics 26: 139-140. [Crossref]
26. Liu X, Wang J, Chen M, Liu S, Yu X et al. (2019)
Combining data from TCGA and GEO databases and reverse transcription
quantitative PCR validation to identify gene prognostic markers in lung cancer.
Onco Targets Ther 12: 709-720. [Crossref]
27. Joyce JA, Pollard JW (2009) Microenvironmental
regulation of metastasis. Nat Rev Cancer 9: 239-252. [Crossref]
28. Quail DF, Joyce JA (2013) Microenvironmental
regulation of tumor progression and metastasis. Nat Med 19: 1423-1437. [Crossref]
29. Hideshima T, Cottini F, Nozawa Y, Seo HS, Ohguchi H et
al. (2017) p53-related protein kinase confers poor prognosis and represents a
novel therapeutic target in multiple myeloma. Blood 129: 1308-1319. [Crossref]
30. Liu B, Li J, Cairns MJ (2014) Identifying miRNAs,
targets and functions. Brief Bioinform 15: 1-19. [Crossref]
31. Bartel DP (2009) MicroRNAs: target recognition and
regulatory functions. Cell 136: 215-233. [Crossref]
32. Hutvagner G, Zamore PD (2002) A microRNA in a
multiple-turnover RNAi enzyme complex. Science 297: 2056-2060. [Crossref]
33. Verma M (2015) The Role of Epigenomics in the Study of
Cancer Biomarkers and in the Development of Diagnostic Tools. Adv Exp Med
Biol 867: 59-80. [Crossref]
34. Lugli A, Zlobec I, Gunthert U, Minoo P, Baker K et al.
(2006) Overexpression of the receptor for hyaluronic acid mediated motility is
an independent adverse prognostic factor in colorectal cancer. Mod Pathol
19: 1302-1309. [Crossref]
35. Koelzer VH, Huber B, Mele V, Iezzi G, Trippel M et al.
(2015) Expression of the hyaluronan-mediated motility receptor RHAMM in tumor
budding cells identifies aggressive colorectal cancers. Hum Pathol 46:
1573-1581. [Crossref]
36. He X, Liao W, Li Y, Wang Y, Chen Q et al. (2015)
Upregulation of hyaluronan-mediated motility receptor in hepatocellular
carcinoma predicts poor survival. Oncol Lett 10: 3639-3646. [Crossref]
37. Yang Y, Han CY, Guan QB, Ruan SL (2018)
Interleukin-17-mediated inflammation promotes nonalcoholic fatty liver disease
in mice with regulation of M1-type macrophage polarization. Zhonghua Gan
Zang Bing Za Zhi 26: 916-921. [Crossref]
38. Abu Halima M, Ayesh BM, Hart M, Alles J, Fischer U et
al. (2019) Differential expression of miR-23a/b- 3p and its target genes in
male patients with subfertility. Fertil Steril 112: 323.e2-335.e2. [Crossref]
39. Truong JL, Liu M, Tolg C, Barr M, Dai C et al. (2019)
Creating a Favorable Micro-Environment for Fat Grafting in a Novel Model of
Radiation Induced Mammary Fat Pad Fibrosis. Plast Reconstr Surg 145: 116-126. [Crossref]
40. Jiao J, Friedman SL, Aloman C (2009) Hepatic fibrosis.
Curr Opin Gastroenterol 25: 223-229. [Crossref]
41. Dutta R, Mahato RI (2017) Recent advances in
hepatocellular carcinoma therapy. Pharmacol Therapeut 173: 106-117. [Crossref]
42. Yang N, Ekanem NR, Sakyi CA, Ray SD (2015)
Hepatocellular carcinoma and microRNA: new perspectives on therapeutics and
diagnostics. Adv Drug Deliv Rev 81: 62-74. [Crossref]
43. Sulaiman SA, Abu N, Ab Mutalib NS, Low TY, Jamal R
(2019) Signatures of gene expression, DNA methylation and microRNAs of hepatocellular
carcinoma with vascular invasion. Future Oncol 15: 2603-2617. [Crossref]
44. Zhang L, Wang Y, Wang L, Yin G, Li W et al. (2018)
miR-23c suppresses tumor growth of human hepatocellular carcinoma by
attenuating ERBB2IP. Biomed Pharmacother 107: 424-432. [Crossref]
45. Devadas K, Biswas S, Haleyurgirisetty M, Ragupathy V,
Wang X et al. (2016) Identification of Host Micro RNAs That Differentiate HIV-1
and HIV-2 Infection Using Genome Expression Profiling Techniques. Viruses
8: 121. [Crossref]
46. Cai Y, Sheng Z, Chen Y, Wang J (2019) LncRNA HMMR-AS1
promotes proliferation and metastasis of lung adenocarcinoma by regulating
MiR-138/sirt6 axis. Aging (Albany NY) 11: 3041-3054. [Crossref]
47. Chu Z P, Dai J, Jia LG, Li J, Zhang Y et al. (2018)
Increased expression of long noncoding RNA HMMR-AS1 in epithelial ovarian
cancer: an independent prognostic factor. Eur Rev Med Pharmacol Sci 22:
8145-8150. [Crossref]
48. Li J, Ji X, Wang H (2018) Targeting Long Noncoding RNA
HMMR-AS1 Suppresses and Radiosensitizes Glioblastoma. Neoplasia 20:
456-466. [Crossref]
49. Liu W, Ma J, Cheng Y, Zhang H, Luo W et al. (2016)
HMMR antisense RNA 1, a novel long noncoding RNA, regulates the progression of
basal-like breast cancer cells. Breast Cancer (Dove Med Press) 8:
223-229. [Crossref]