Genetic variants of the Nav 1.5 sodium channel and its therapeutic implications.

• Grant number: 18/20777-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): May 01, 2019
• Effective date (End): June 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Danilo Roman Campos
• Grantee: Julliane Vasconcelos Joviano dos Santos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Abstract: The cardiac cycle depends on the proper function of the excitation contraction coupling in ventricular myocytes (VMs), which has ion channels as primary player present on cell membrane of VMs. Nav 1.5, encoded by SCN5A gene, is the primary cardiac sodium channel. Sodium current (INa) has two components: the transient peak (INa-P) and the late (INa-L). In the cardiac cycle, acquired and inherited channelopathies usually causes altered action potential (AP) in VMs. Polymorphism are defined by replacement of one nucleotide in the DNA sequence observed in e 1% of population. In Brazil, due to migration, it is observed strong influence of African, European and Asian ethnics, which are found to have S524Y, S1103Y, R1193Q e V1951L polymorphisms in Nav 1.5. Polymorphisms may lead to altered biophysical and pharmacological properties of Nav 1.5 and, once associated to other mutations, may cause disease linked mutation (e.g Long QT Syndrome). Despite of great important of Nav 1.5 in the cardiac cycle, it is not fully understood how polymorphism impacts on biophysical and pharmacological properties of Nav 1.5. Thus, we intent to: 1) understand how ethnic linked polymorphism impact on biophysical and 2) pharmacological properties (potency, efficacy and selectivity) of antiarrhythmic drugs (amiodarone and ranolazine) on Nav 1.5. In order to achieve the main goal we will take advantage of: point mutation, heterologous expression and patch-clamp technique. In the future we intent to study arrhythmic disease related mutation found in Brazilian population and how it influences antiarrhythmic therapy. The proposed project is associated to Young Investigation Project of the Principal Investigation.

Scientific publications

(12)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

JOVIANO-SANTOS, JULLIANE VASCONCELOS; SANTOS-MIRANDA, ARTUR; ROMAN-CAMPOS, DANILO. Cardiac electrical remodeling and neurodegenerative diseases association. Life Sciences, v. 267, FEB 15 2021. (19/21304-4, 18/22830-9, 18/20777-3, 14/09861-1)

JOCA, HUMBERTO C.; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, V, JULLIANE; MAIA-JOCA, REBECA P. M.; BRUM, PATRICIA C.; WILLIAMS, GEORGE S. B.; CRUZ, JADER S.. Chronic Sympathetic Hyperactivity Triggers Electrophysiological Remodeling and Disrupts Excitation-Contraction Coupling in Heart. SCIENTIFIC REPORTS, v. 10, n. 1, MAY 14 2020. (18/20777-3, 18/22830-9)

SANTOS-MIRANDA, ARTUR; COSTA, ALEXANDRE D.; JOVIANO-SANTOS, V, JULLIANE; RHANA, PAULA; BRUNO, ALEXANDRE SANTOS; ROCHA, PETER; CAU, STEFANY BRUNO; VIEIRA, LEDA Q.; CRUZ, JADER S.; ROMAN-CAMPOS, DANILO. Inhibition of calcium/calmodulin (Ca2+/CaM)-Calcium/calmodulin-dependent protein kinase II (CaMKII) axis reduces in vitro and ex vivo arrhythmias in experimental Chagas disease. FASEB JOURNAL, v. 35, n. 10, OCT 2021. (19/21304-4, 18/20777-3, 18/22830-9)

ROMAN-CAMPOS, DANILO; SALES-JUNIOR, POLICARPO; COSTA, ALEXANDRE D.; SOUZA, DIEGO SANTOS; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE, V; ROPERT, CATHERINE; CRUZ, JADER S.. Impact of IFN-gamma Deficiency on the Cardiomyocyte Function in the First Stage of Experimental Chagas Disease. MICROORGANISMS, v. 10, n. 2, p. 7-pg., 2022-02-01. (19/18918-0, 18/22830-9, 19/21304-4, 18/20777-3)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE VASCONCELOS; RIBEIRO, GRAZIELLE ALVES; BOTELHO, ANA FLAVIA M.; ROCHA, PETER; VIEIRA, LEDA QUERCIA; CRUZ, JADER SANTOS; ROMAN-CAMPOS, DANILO. Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. PLOS PATHOGENS, v. 16, n. 3, MAR 2020. (18/20777-3, 14/09861-1, 18/22830-9)

ROMAN-CAMPOS, DANILO; SALES-JUNIOR, POLICARPO; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, V, JULLIANE; ROPERT, CATHERINE; CRUZ, JADER S.. Deletion of inducible nitric oxide synthase delays the onset of cardiomyocyte electrical remodeling in experimental Chagas disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1866, n. 12, DEC 1 2020. (14/09861-1, 19/21304-4, 18/22830-9, 18/20777-3)

JOVIANO-SANTOS, JULLIANE V.; VALADAO, PRISCILA A. C.; MAGALHAES-GOMES, MATHEUS P. S.; FERNANDES, LORENA F.; DINIZ, DANUZA M.; MACHADO, THATIANE C. G.; SOARES, KIVIA B.; LADEIRA, MARINA S.; MIRANDA, ALINE S.; MASSENSINI, ANDRE R.; et al. Protective effect of a spider recombinant toxin in a murine model of Huntington's disease. Neuropeptides, v. 85, FEB 2021. (18/20777-3)

TEIXEIRA-FONSECA, JORGE LUCAS; SANTOS-MIRANDA, ARTUR; DA SILVA, JOAB BARBOSA; MARQUES, LEISIANE PEREIRA; JOVIANO-SANTOS, JULLIANE VASCONCELOS; CHAVES NUNES, PAULA IDMA; ROMAN-CAMPOS, DANILO; SANTANA GONDIM, ANTONIO NEI. Eugenol interacts with cardiac sodium channel and reduces heart excitability and arrhythmias. Life Sciences, v. 282, OCT 1 2021. (18/22830-9, 18/20777-3, 19/21304-4)

JOVIANO-SANTOS, V, J.; SANTOS-MIRANDA, A.; NERI, E. A.; FONSECA-ALANIZ, M. H.; KRIEGER, J. E.; PEREIRA, A. C.; ROMAN-CAMPOS, D.. SCN5A compound heterozygosity mutation in Brugada syndrome: Functional consequences and the implication for pharmacological treatment. Life Sciences, v. 278, AUG 1 2021. (19/21304-4, 14/09861-1, 18/20777-3)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, V. JULLIANE; CRUZ-NASCIMENTO, TAYNARA; NERI, ELIDA ADALGISA; SOUZA, DIEGO SANTOS; MARQUES, LEISIANE PEREIRA; KRIEGER, JOSE E.; ROMAN-CAMPOS, DANILO. The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells. Toxicology Letters, v. 359, p. 10-pg., 2022-04-15. (18/22830-9, 19/18918-0, 21/05584-7, 19/21304-4, 20/14635-1, 18/20777-3)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE V.; SARMENTO, JAQUELINE O.; COSTA, ALEXANDRE D.; SOARES, ALLYSSON T. C.; MACHADO, FABIANA S.; CRUZ, JADER S.; ROMAN-CAMPOS, DANILO. A novel substrate for arrhythmias in Chagas disease. PLoS Neglected Tropical Diseases, v. 15, n. 6, JUN 2021. (19/21304-4, 14/09861-1, 18/20777-3, 18/22830-9, 20/09403-4)

DA SILVA, MARIA VITORIA; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE, V; SOUZA, DIEGO SANTOS; MARQUES, LEISIANE PEREIRA; SARMENTO, JAQUELINE OLIVEIRA; BESERRA, SAMUEL SANTOS; ROMAN-CAMPOS, DANILO. The insecticide beta-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype. Clinical Science, v. 136, n. 5, p. 15-pg., 2022-03-01. (21/05584-7, 19/18918-0, 18/20777-3, 18/22830-9, 20/09403-4, 19/21304-4)