“Overexpression of IP3-released inositol 1,4,5-triphosphate receptor-binding protein (IP3R) (IRBIT) induces the development of cardiac hypertrophy

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

La Plata

Congreso; Reunión anual ISHR Latinoamérica; 2022

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 establish its pathophysiological 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