Author + information
- Yuriana Oropeza,
- Judith Bernal-Ramírez,
- Eduardo Reyes-Alvarez,
- Jesús Garza-López and
- Gerardo García-Rivas
Background: Ventricular arrhythmias are prevalent in cardiac diseases, including heart failure and myocardial ischemia where calcium mishandling appears as an underlying mechanism. Recently, it has been suggested that mitochondria importantly contributes as cytosolic Ca2+ buffer in a beat-to-beat base through mitochondrial calcium uniporter channel (MCU). Despite evidence obtained by pharmacological and molecular strategies, MCU contribution in Ca2+ handling and their role in arrhythmogenesis is still under discussion.
Methods: Isolated adult rat and H9c2 cardiomyocytes were treated with Ru360 (a potent and specific MCU inhibitor) or siRNA targeting-MCU was used to reduce the MCU expression. Mitochondrial transport, cytosolic Ca2+ dynamics, sarcoplasmic reticulum (SR) Ca2+ load and spontaneous Ca2+ release (SCR) were analyzed under confocal microscopy.
Results: The half maximal inhibitory concentration (IC50) of Ru360 for the inhibition of mitochondrial Ca2+ uptake into H9c2 cardiomyocytes was 305 nM. Ru360-treated adult cardiomyocytes increase the cytosolic Ca2+ transient amplitude in dose-dependent manner. Cytoplasmic Ca2+ peaks are 30% enhanced by MCU-siRNA silencing. Accordingly, the extent of contraction is augmented by MCU inhibition. Remarkably, SCR events were more frequent in Ru360- treated cardiomyocytes, albeit the SR load was unchanged with respect to untreated cells.
Conclusions: MCU pharmacological inhibition or siRNA-silencing increases cytosolic Ca2+, suggesting that mitochondria significantly contribute to buffering the amplitude of systolic Ca2+ peak and cell shortening. In these conditions, mitochondrial Ca2+ homeostasis emerges as an important regulatory mechanism of cardiac physiology that might be substrate for ventricular arrhythmias.
Poster Hall, Hall C
Friday, March 17, 2017, 3:45 p.m.-4:30 p.m.
Session Title: Arrhythmias and Clinical EP: Basic 2
Abstract Category: 4. Arrhythmias and Clinical EP: Basic
Presentation Number: 1152-113
- 2017 American College of Cardiology Foundation