The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture and Transfection
2.2. Patch-Clamp Experiments
2.3. Data and Statistical Analyses
2.4. Chemicals
3. Results
3.1. Characteristics of the ∆KPQ hNaV1.5 Currents
3.2. Effects of Hesperetin on ∆KPQ hNaV1.5 Currents
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Adabag, A.S.; Luepker, R.V.; Roger, V.L.; Gersh, B.J. Sudden cardiac death: Epidemiology and risk factors. Nat. Rev. Cardiol. 2010, 7, 216–225. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Priori, S.G.; Schwartz, P.J.; Napolitano, C.; Bloise, R.; Ronchetti, E.; Grillo, M.; Vicentini, A.; Spazzolini, C.; Nastoli, J.; Bottelli, G.; et al. Risk stratification in the long-QT syndrome. N. Engl. J. Med. 2003, 348, 1866–1874. [Google Scholar] [CrossRef] [PubMed]
- Schwartz, P.J.; Stramba-Badiale, M.; Crotti, L.; Pedrazzini, M.; Besana, A.; Bosi, G.; Gabbarini, F.; Goulene, K.; Insolia, R.; Mannarino, S.; et al. Prevalence of the congenital long-QT syndrome. Circulation 2009, 120, 1761–1767. [Google Scholar] [CrossRef] [PubMed]
- Winkel, B.G.; Larsen, M.K.; Berge, K.E.; Leren, T.P.; Nissen, P.H.; Olesen, M.S.; Hollegaard, M.V.; Jespersen, T.; Yuan, L.; Nielsen, N.; et al. The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases. J. Cardiovasc. Electrophysiol. 2012, 23, 1092–1098. [Google Scholar] [CrossRef] [PubMed]
- Abu-Zeitone, A.; Peterson, D.R.; Polonsky, B.; McNitt, S.; Moss, A.J. Efficacy of different β-blockers in the treatment of long QT syndrome. J. Am. Coll. Cardiol. 2014, 64, 1352–1358. [Google Scholar] [CrossRef] [Green Version]
- Ackerman, M.J.; Priori, S.G.; Dubin, A.M.; Kowey, P.; Linker, N.J.; Slotwiner, D.; Triedman, J.; Van Hare, G.F.; Gold, M.R. β-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: Are all beta-blockers equivalent? Heart Rhythm. 2017, 14, e41–e44. [Google Scholar] [CrossRef] [Green Version]
- Calvillo, L.; Spazzolini, C.; Vullo, E.; Insolia, R.; Crotti, L.; Schwartz, P.J. Propranolol prevents life-threatening arrhythmias in LQT3 transgenic mice: Implications for the clinical management of LQT3 patients. Heart Rhythm. 2014, 11, 126–132. [Google Scholar] [CrossRef] [Green Version]
- Priori, S.G.; Blomström-Lundqvist, C.; Mazzanti, A.; Blom, N.; Borggrefe, M.; Camm, J.; Elliott, P.M.; Fitzsimons, D.; Hatala, R.; Hindricks, G.; et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the Europe. Eur. Heart J. 2015, 36, 2793–2867. [Google Scholar] [CrossRef] [Green Version]
- Schwartz, P.J.; Ackerman, M.J. The long QT syndrome: A transatlantic clinical approach to diagnosis and therapy. Eur. Heart J. 2013, 34, 3109–3116. [Google Scholar] [CrossRef] [Green Version]
- Wilde, A.A.M.; Moss, A.J.; Kaufman, E.S.; Shimizu, W.; Peterson, D.R.; Benhorin, J.; Lopes, C.; Towbin, J.A.; Spazzolini, C.; Crotti, L.; et al. Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. Circulation 2016, 134, 872–882. [Google Scholar] [CrossRef] [Green Version]
- Ahn, J.; Kim, H.J.; Choi, J.-I.; Lee, K.N.; Shim, J.; Ahn, H.S.; Kim, Y.-H. Effectiveness of β-blockers depending on the genotype of congenital long-QT syndrome: A meta-analysis. PLoS ONE 2017, 12, e0185680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fabritz, L.; Damke, D.; Emmerich, M.; Kaufmann, S.G.; Theis, K.; Blana, A.; Fortmüller, L.; Laakmann, S.; Hermann, S.; Aleynichenko, E.; et al. Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3. Cardiovasc. Res. 2010, 87, 60–72. [Google Scholar] [CrossRef] [PubMed]
- Moss, A.J.; Zareba, W.; Hall, W.J.; Schwartz, P.J.; Crampton, R.S.; Benhorin, J.; Vincent, G.M.; Locati, E.H.; Priori, S.G.; Napolitano, C.; et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000, 101, 616–623. [Google Scholar] [CrossRef] [Green Version]
- Priori, S.G.; Napolitano, C.; Schwartz, P.J.; Grillo, M.; Bloise, R.; Ronchetti, E.; Moncalvo, C.; Tulipani, C.; Veia, A.; Bottelli, G.; et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004, 292, 1341–1344. [Google Scholar] [CrossRef] [Green Version]
- Schwartz, P.J.; Priori, S.G.; Spazzolini, C.; Moss, A.J.; Vincent, G.M.; Napolitano, C.; Denjoy, I.; Guicheney, P.; Breithardt, G.; Keating, M.T.; et al. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation 2001, 103, 89–95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shimizu, W.; Antzelevitch, C. Differential effects of β-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J. Am. Coll. Cardiol. 2000, 35, 778–786. [Google Scholar] [CrossRef] [Green Version]
- Mazzanti, A.; Maragna, R.; Faragli, A.; Monteforte, N.; Bloise, R.; Memmi, M.; Novelli, V.; Baiardi, P.; Bagnardi, V.; Etheridge, S.P.; et al. Gene-Specific Therapy with Mexiletine Reduces Arrhythmic Events in Patients with Long QT Syndrome Type 3. J. Am. Coll. Cardiol. 2016, 67, 1053–1058. [Google Scholar] [CrossRef]
- Lei, M.; Wu, L.; Terrar, D.A.; Huang, C.L.-H. Modernized Classification of Cardiac Antiarrhythmic Drugs. Circulation 2018, 138, 1879–1896. [Google Scholar] [CrossRef]
- Roden, D.M. Pharmacology and Toxicology of NaV1.5-Class 1 anti-arrhythmic drugs. Card. Electrophysiol. Clin. 2014, 6, 695–704. [Google Scholar] [CrossRef] [Green Version]
- Pérez-Riera, A.R.; Barbosa-Barros, R.; Daminello Raimundo, R.; da Costa de Rezende Barbosa, M.P.; Esposito Sorpreso, I.C.; de Abreu, L.C. The congenital long QT syndrome Type 3: An update. Indian Pacing Electrophysiol. J. 2017, 18, 25–35. [Google Scholar] [CrossRef] [PubMed]
- Ruan, Y.; Denegri, M.; Liu, N.; Bachetti, T.; Seregni, M.; Morotti, S.; Severi, S.; Napolitano, C.; Priori, S.G. Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3. Circ. Res. 2010, 106, 1374–1383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, W.; Mazzanti, A.; Voelker, T.L.; Hou, P.; Moreno, J.D.; Angsutararux, P.; Naegle, K.M.; Priori, S.G.; Silva, J.R. Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation. Circ. Res. 2019, 124, 539–552. [Google Scholar] [CrossRef] [PubMed]
- Dainis, A.M.; Ashley, E.A. Cardiovascular Precision Medicine in the Genomics Era. JACC Basic Transl. Sci. 2018, 3, 313–326. [Google Scholar] [CrossRef] [PubMed]
- Joyner, M.J. Precision Medicine, Cardiovascular Disease and Hunting Elephants. Prog. Cardiovasc. Dis. 2016, 58, 651–660. [Google Scholar] [CrossRef]
- Bohnen, M.S.; Peng, G.; Robey, S.H.; Terrenoire, C.; Iyer, V.; Sampson, K.J.; Kass, R.S. Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol. Rev. 2017, 97, 89–134. [Google Scholar] [CrossRef] [Green Version]
- Veerman, C.C.; Wilde, A.A.M.; Lodder, E.M. The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology. Gene 2015, 573, 177–187. [Google Scholar] [CrossRef]
- Zimmer, T.; Surber, R. SCN5A channelopathies—An update on mutations and mechanisms. Prog. Biophys. Mol. Biol. 2008, 98, 120–136. [Google Scholar] [CrossRef]
- Kambouris, N.G.; Nuss, H.B.; Johns, D.C.; Tomaselli, G.F.; Marban, E.; Balser, J.R. Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. Circulation 1998, 97, 640–644. [Google Scholar] [CrossRef] [Green Version]
- Alvarez-Collazo, J.; Lopez-Requena, A.; Galan, L.; Talavera, A.; Alvarez, J.L.; Talavera, K. The citrus flavanone hesperetin preferentially inhibits slow-inactivating currents of a long QT syndrome type 3 syndrome Na+ channel mutation. Br. J. Pharmacol. 2019, 176, 1090–1105. [Google Scholar] [CrossRef] [Green Version]
- Fredj, S.; Sampson, K.J.; Liu, H.; Kass, R.S. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: Evidence for site of action. Br. J. Pharmacol. 2006, 148, 16–24. [Google Scholar] [CrossRef]
- Wissenbach, U.; Bödding, M.; Freichel, M.; Flockerzi, V. Trp12, a novel Trp related protein from kidney. FEBS Lett. 2000, 485, 127–134. [Google Scholar] [CrossRef]
- Talavera, K.; Janssens, A.; Klugbauer, N.; Droogmans, G.; Nilius, B. Pore structure influences gating properties of the T-type Ca2+ channel α1G. J. Gen. Physiol. 2003, 121, 529–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Remme, C.A. Cardiac sodium channelopathy associated with SCN5A mutations: Electrophysiological, molecular and genetic aspects. J. Physiol. 2013, 591, 4099–4116. [Google Scholar] [CrossRef]
- Barber, M.J.; Wendt, D.J.; Starmer, C.F.; Grant, A.O. Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs. J. Clin. Investig. 1992, 90, 368–381. [Google Scholar] [CrossRef] [Green Version]
- Belardinelli, L.; Liu, G.; Smith-Maxwell, C.; Wang, W.-Q.; El-Bizri, N.; Hirakawa, R.; Karpinski, S.; Li, C.H.; Hu, L.; Li, X.-J.; et al. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J. Pharmacol. Exp. Ther. 2013, 344, 23–32. [Google Scholar] [CrossRef] [PubMed]
- Antzelevitch, C.; Nesterenko, V.; Shryock, J.C.; Rajamani, S.; Song, Y.; Belardinelli, L. The role of late INa in development of cardiac arrhythmias. Handb. Exp. Pharmacol. 2014, 221, 137–168. [Google Scholar]
- Sicouri, S.; Belardinelli, L.; Antzelevitch, C. Antiarrhythmic effects of the highly selective late sodium channel current blocker GS-458967. Heart Rhythm. 2013, 10, 1036–1043. [Google Scholar] [CrossRef] [Green Version]
- Coraboeuf, E.; Deroubaix, E.; Coulombe, A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am. J. Physiol. 1979, 236, H561–H567. [Google Scholar] [CrossRef]
- Miller, D.; Wang, L.; Zhong, J. Sodium channels, cardiac arrhythmia, and therapeutic strategy. Adv. Pharmacol. 2014, 70, 367–392. [Google Scholar]
- Carnevale, V. Protonation underlies tonic vs. use-dependent block. Proc. Natl. Acad. Sci USA 2018, 115, 3512–3514. [Google Scholar] [CrossRef] [Green Version]
- Gamal El-Din, T.M.; Lenaeus, M.J.; Zheng, N.; Catterall, W.A. Fenestrations control resting-state block of a voltage-gated sodium channel. Proc. Natl. Acad. Sci USA 2018, 115, 13111–13116. [Google Scholar] [CrossRef] [Green Version]
- Kaczmarski, J.A.; Corry, B. Investigating the size and dynamics of voltage-gated sodium channel fenestrations. Channels 2014, 8, 264–277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Condition | GM (nS/pF) | VNa (mV) | Vact (mV) | sact (mV) | Vinac (mV) | sinac (mV) |
---|---|---|---|---|---|---|
WT control | 2.0 ± 0.6 | 42.6 ± 1.2 | −35.8 ± 1.1 | 5.5 ± 0.7 | −70.2 ± 0.4 | 6.6 ± 0.4 |
WT HSP | 0.5 ± 0.1 1 | 39.3 ± 2.9 | −30.2 ± 0.6 | 5.6 ± 0.5 | −86.0 ± 0.5 1 | 5.1 ± 0.5 |
∆KPQ control | 1.6 ± 0.3 | 44.8 ± 1.0 | −29.3 ± 0.4 | 6.4 ± 0.3 | −82.6 ± 0.3 | 5.9 ± 0.3 |
∆KPQ HSP | 0.8 ± 0.1 1 | 42.3 ± 0.6 | −29.1 ± 0.3 | 6.1 ± 0.2 | −84.9 ± 0.5 | 5.8 ± 0.4 |
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Alvarez-Collazo, J.; López-Requena, A.; Alvarez, J.L.; Talavera, K. The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome. Biomolecules 2020, 10, 952. https://doi.org/10.3390/biom10060952
Alvarez-Collazo J, López-Requena A, Alvarez JL, Talavera K. The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome. Biomolecules. 2020; 10(6):952. https://doi.org/10.3390/biom10060952
Chicago/Turabian StyleAlvarez-Collazo, Julio, Alejandro López-Requena, Julio L. Alvarez, and Karel Talavera. 2020. "The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome" Biomolecules 10, no. 6: 952. https://doi.org/10.3390/biom10060952
APA StyleAlvarez-Collazo, J., López-Requena, A., Alvarez, J. L., & Talavera, K. (2020). The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome. Biomolecules, 10(6), 952. https://doi.org/10.3390/biom10060952