Calcineurin/P38MAPK/HSP27-dependent pathways are involved in the attenuation of postischemic mitochondrial injury afforded by sodium bicarbonate co-transporter (NBCe1) inhibition

CIOCCI PARDO, ALEJANDRO; GONZÁLEZ ARBELÁEZ, LUISA F.; FANTINELLI, JULIANA C.; AIELLO, ERNESTO A.; MOSCA, SUSANA M.

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2019 vol. 161 p. 26 - 36

0006-2952

The electrogenic sodium bicarbonate co-transporter isoform 1 (NBCe1) plays an important role in ischemiareperfusioninjury. The cardioprotective action of an antibody directed to the extracellular loop 3 (a-L3) ofNBCe1 was previously demonstrated by us. However, the role of a-L3 on mitochondrial post-ischemic alterationshas not yet been determined. In this study, we aimed to elucidate the effects of a-L3 on post-ischemic mitochondrialstate and dynamics analysing the involved mechanisms. Isolated rat hearts were assigned to thefollowing groups: 1) Non-ischemic control (NIC): 110 min of perfusion; 2) Ischemic control (IC): 30 min of globalischemia and 60 min of reperfusion (R); 3) a-L3: a-L3 was administered during the initial 10 min of R; 4) SB+a-L3: SB202190 (p38MAPK inhibitor) plus a-L3. Infarct size (IS) was measured by TTC staining. Developedpressure (LVDP), maximal velocities of rise and decay of LVP (+dP/dt max, −dP/dt max) and end-diastolicpressure (LVEDP) of the left ventricle were used to assess systolic and diastolic function. Mitochondrial Ca2+response (CaR), Ca2+ retention capacity (CRC), membrane potential (ΔΨm) and MnSOD levels were measured.The expression of P-p38MAPK, calcineurin, P-HSP27, P-Drp1, Drp1, and OPA1 were determined. a-L3 decreasedIS, improved post-ischemic recovery of myocardial function, increased P-p38MAPK, P-HSP27, P-Drp1, cytosolicDrp1, and OPA1 expression and decreased calcineurin. These effects were abolished by p38MAPK inhibitionwith SB. These data show that NBCe1 inhibition by a-L3 limits the cell death, improves myocardial post-ischemiccontractility and mitochondrial state and dynamic through calcium decrease/calcineurin inhibition-mediatedp38MAPK activation and p38MAPK/HSP27-dependent pathways. Thus, we demonstrated that a-L3 is a potentialtherapeutic strategy in post-ischemic alterations.