Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and NRF2 Activation

Almudena Val-Blasco; Patricia Prieto; Rafael Iñigo Jaén; Marta Gil-Fernández; Marta Pajares; Nieves Domenech; Verónica Terrón; María Tamayo; Inmaculada Jorge; Jesús Vázquez; Andrea Bueno-Sen; María Teresa Vallejo-Cremades; Jorge Pombo-Otero; Sergio Sanchez-García; Gema Ruiz-Hurtado; Ana María Gómez; Carlos Zaragoza; María Generosa Crespo-Leiro; Eduardo López-Collazo; Antonio Cuadrado; Carmen Delgado; Lisardo Boscá; María Fernández-Velasco

doi:10.1016/j.jacbts.2022.01.009

Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca²⁺ Handling and NRF2 Activation

JACC Basic Transl Sci. 2022 May 18;7(6):544-560. doi: 10.1016/j.jacbts.2022.01.009. eCollection 2022 Jun.

Authors

Almudena Val-Blasco^{1

2}, Patricia Prieto^{3

4}, Rafael Iñigo Jaén⁵, Marta Gil-Fernández^{1

5}, Marta Pajares^{5

6}, Nieves Domenech^{4

7}, Verónica Terrón¹, María Tamayo⁵, Inmaculada Jorge^{4

8}, Jesús Vázquez^{4

8}, Andrea Bueno-Sen¹, María Teresa Vallejo-Cremades⁹, Jorge Pombo-Otero⁷, Sergio Sanchez-García⁵, Gema Ruiz-Hurtado^{4

10}, Ana María Gómez², Carlos Zaragoza^{4

11}, María Generosa Crespo-Leiro^{4

7}, Eduardo López-Collazo^{1

12}, Antonio Cuadrado^{1

5

6

13}, Carmen Delgado^{4

5}, Lisardo Boscá^{4

5}, María Fernández-Velasco^{1

4}

Affiliations

¹ Innate Immune Response Group, La Paz University Hospital, Instituto de Investigación Biomédica del Hospital La Paz (IdiPAZ), Madrid, Spain.
² Signaling and Cardiovascular Pathophysiology, Unite Mixte de Recherche S 1180, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Paris, France.
³ Pharmacology, Pharmacognosy, and Botany Department, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain.
⁴ Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
⁵ Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Autonomous University of Madrid (UAM), Madrid, Spain.
⁶ Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Madrid, Spain.
⁷ Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Sergas, Universidad da Coruña, A Coruña, Spain.
⁸ Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
⁹ Molecular Image and Immunohistochemistry Unit, IdiPAZ, La Paz University Hospital, Madrid, Spain.
¹⁰ Cardiorenal Translational Laboratory, Institute of Research i+12, CIBERCV, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹¹ Departamento de Cardiología, Unidad de Investigación Mixta Universidad Francisco de Vitoria, Madrid, Spain.
¹² Centro de Investigación Biomédica en Res de Enfermedades Respiratorias, Madrid, Spain.
¹³ Department of Biochemistry, Faculty of Medicine, UAM, Madrid, Spain.

Abstract

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca²⁺ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.

Keywords: 8OHdG, 8-hydroxy-2'-deoxyguanosine; BML-111, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester; Ctrl, control; Cys, cysteine; EAM, experimental autoimmune myocarditis; EC, excitation-contraction; Epi, 15-epi-lipoxin A4; LXA4, lipoxin A4; Lut, luteolin; NRF2; NRF2, nuclear factor erythroid-derived 2-like 2; SCR, spontaneous diastolic Ca2+ release; SERCA2A; SERCA2A, sarcoplasmic reticulum–adenosine triphosphatase 2A; SPM, specialized proresolving mediator; SR, sarcoplasmic reticulum; Veh, vehicle; calcium handling; mRNA, messenger RNA; myocarditis; pro-resolving mediators.