Abstract 389: Alterations of Mitochondrial Calcium Handling in Heart Failure
Heart failure (HF) and sudden cardiac death (SCD) are major public health concerns that are increasing in incidence, yet the mechanisms underlying SCD in patients with HF are poorly understood. In a novel guinea pig model of HF/SCD, we showed that in vivo treatment with a mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor attenuates cardiac remodeling, preserves cardiac contractile function, and improves survival, supporting a critical role for altered mitochondrial Ca2+ dynamics in the pathophysiology. Here, we investigate whether the intrinsic mitochondrial Ca2+ transport rates are altered in this HF model.
Methods: Ascending aortic constriction, combined with daily i.p. injection of isoproterenol (ISO), were used to induce HF (ACi) with acquired long QT. This group was compared with animals subjected to aortic constriction alone (AC), or sham-operated animals with (SHAMi) or without (SHAM) ISO treatment. Ca2+ Green-5N was used to measure total mitochondrial Ca2+ uptake and to quantify mitochondrial Ca2+ influx and efflux rates in isolated cardiac mitochondria.
Results: Both the total mitochondrial Ca2+ load and the Ca2+ capacity prior to triggering permeability transition pore (mPTP) opening were reduced in HF mitochondria (5mM NaCl present). Mitochondrial Ca2+ fluxes, individually measured with sequential additions of 15μM free Ca2+, 10nM Ru360 and 5mM NaCl, showed that initial Ca2+ uptake rate through the mitochondrial Ca2+ uniporter (mCU: 0.55 nmol/sec/mg) was not significantly changed in HF; however, the Ca2+ extrusion rate through mNCE was larger in HF (AC:0.022 nmol/sec/mg; SHAM:0.018; ACi:0.013; SHAMi:0.009), but with a lower affinity for Na+. Interestingly, Na+-independent efflux via mPTP increased in HF (AC:0.0040 nmol/sec/mg; SHAM:0.0022; ACi:0.0013; SHAMi:0.012). Mitochondria from failing hearts also showed decreased respiration and increased ROS emission.
Conclusions: The data indicate that an increase of intrinsic Ca2+ efflux and the increase in cytoplasmic Na+ in HF could both contribute to blunted mitochondrial Ca2+ in HF, which will affect cardiac energetics and ROS balance. Inhibitors of mNCE or mPTP are thus proposed to be therapeutic interventions that would improve mitochondrial Ca2+ balance and function in HF.
Author Disclosures: A. Wei: None. T. Liu: None. B. O’Rourke: None.
- © 2015 by American Heart Association, Inc.