Involvement of the Ca2+/ Calmodulin/CAMKII signaling axis in the electrical and contractile dysfunctions of the heart in the chronic phase of Chagas Disease

• Grant number: 18/22830-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2019
• End date: July 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Danilo Roman Campos
• Grantee: Artur Santos Miranda
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Chagas' disease (CD) affects 6-7 million people worldwide. Among its clinical manifestations, chagasic cardiopathy is the most common and severe form and it is currently one of the main causes of heart failure (HF) and sudden death in Latin America. Chronic symptomatic patients often display hypertrophy, arrhythmias and ultimately HF, which makes the treatment ineffective, especially with combined complications. Our research group has provided solid evidences for impaired electrical, contractile and intracellular Ca2+ handling in infected cardiomyocytes. However, the molecular mechanisms that trigger the cell programming preceding such changes are still unclear. In this context, the Ca2+/Calmodulin/Calmodulin kinase II (CAMKII) signaling axis may play an important role. The hyperactivation of this axis is already linked to arrhythmias and HF. In addition, this axis is known to modulate several ion channels, transporters and contractile proteins in cardiomyocytes. In this project, we aimed to elucidate the involvement of this axis in electrical and contractile dysfunctions of the heart during the chronic phase of CD. In addition, we objective to determine if manipulation of CAMKII activity may be a promising target in the treatment of Chagas' heart disease. We are going to take advantage of our murine model of Chagas disease, which present cardiac symptoms of chronical phase at 200 days post-infection. At the and we are going to postulate whether CAMKII inhibitors are potential therapeutic agents to treat chagasic cardiomyopathy.

Scientific publications

(13)

(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)

SANTOS-MIRANDA, ARTUR; CHEN, HONGHONG; CHEN, ROBERT C.; ODOKO-ISHIMOTO, MAMIKO; AOYAMA, HIROSHI; BAI, DONGLIN. The amino terminal domain plays an important role in transjunctional voltage-dependent gating kinetics of Cx45 gap junctions. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v. 143, p. 71-84, JUN 2020. (18/22830-9)

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)

BESERRA, SAMUEL SANTOS; SANTOS-MIRANDA, ARTUR; SARMENTO, JAQUELINE OLIVEIRA; MIRANDA, VICTOR MARTINS; ROMAN-CAMPOS, DANILO. Effects of amiodarone on rodent ventricular cardiomyocytes: Novel perspectives from a cellular model of Long QT Syndrome Type 3. Life Sciences, v. 255, AUG 15 2020. (18/22830-9)

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)

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)

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)

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)

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)

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)

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)

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)

DA SILVA, AGATHA RIBEIRO; NERI, ELIDE A.; TURACA, LAURO THIAGO; DARIOLLI, RAFAEL; FONSECA-ALANIZ, MIRIAM H.; SANTOS-MIRANDA, ARTUR; ROMAN-CAMPOS, DANILO; VENTURINI, GABRIELA; KRIEGER, JOSE E.. NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro. SCIENTIFIC REPORTS, v. 10, n. 1, p. 18-pg., 2020-09-30. (19/21304-4, 14/24577-8, 18/22830-9, 15/50216-5, 17/05829-4, 13/17368-0, 14/09861-1)