Pathophysiological role of inositol 1, 4, 5-triphosphate receptor (IP3R) binding protein released with IP3 (IRBIT) in the myocardium.

DI MATTÍA RA; CIARROCCHI S; GALLO D; BLANCO PG; PORTIANSKY EL; VALVERDE CA; BLECKWEDEL F; ZELARAYAN L; AIELLO EA; ORLOWSKI A

Congreso; Reunión Anual de Sociedades de Biociencias 2022; 2022

SAFIS-SAIC

“Overexpression of IP3-released inositol 1,4,5-triphosphate receptor-binding protein (IP3R) (IRBIT) induces the development of cardiac hypertrophy”Di Mattia RA1, Ciarrocchi S1, Gallo D1, Blanco PG2, Portiansky EL3, Valverde CA1, Bleckwedel F4, Zelarayán L4, Aiello EA1, Orlowski A11Centro de Investigaciones Cardiovasculares “Dr. Horacio Cingolani”, Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET. La Plata, Argentina.2Servicio de Cardiología, Facultad de Veterinaria, Universidad Nacional de La Plata. La Plata, Argentina.3Laboratorio de Análisis de Imágenes, Facultad de Veterinaria, Universidad Nacional de La Plata-CONICET. La Plata, Argentina.4Instituto de Farmacología y Toxicología, Centro Médico Universitario Goettingen. Goettingen, Alemania.Introduction: IP3R binding protein released with IP3 (IRBIT) was originally identified as a competitive inhibitor of the mentioned receptor. When IP3 concentration raises in response to GPCR activation, IRBIT is released from IP3Rs and activates several ion transporters, including Na+/HCO3- cotransporters NBC, Na+/H+ exchanger NHE3, Cl− channel CFTR and Cl−/HCO3− exchanger Slc26a6.Aims: Although IRBIT heart expression has been reported, its function in cardiac tissue is unknown. Thus, we aimed to study the cardiac effects of overexpressing IRBIT to stablish its physiopathological role.Experimental design: 3 months-old male mice were transduced (1x1012 vp/kg) with a cardiotropic adenoassociated virus to achieve IRBIT overexpression (AAV9-IRBIT-mCherry), using AAV9-mCherry as control. Echocardiography and electrocardiography analysis were performed and mice were sacrificed after a month. IRBIT expression was assessed in two cardiac hypertrophy models: spontaneously hypertensive rats (SHR) and mice with transaortic constriction (TAC). Data is expressed as mean±SEM. We used Shapiro-Wilk normality test and Student's t-test or two-way ANOVA test as was needed. For non-normal populations, we used Mann-Whitney test.Results: IRBIT overexpressed mice showed an increase in left ventricular mass index (LVMI) and wall thickness measured by echocardiography (LVMI, 28 days: AAV9-mCherry: 2.81±0.22, n=7; AAV9-IRBIT-mCherry*: 3.77±0.32 n=10; p