ARTICLE: MCU Overexpression Rescues Inotropy and Reverses Heart Failure by Reducing SR Ca2+ Leak
AUTHORS: Ting Liu, Ni Yang, Agnieszka Sidor and Brian O'Rourke
JOURNAL: Circ Res. 2021 Feb 1. doi: 10.1161/CIRCRESAHA.120.318562. Online ahead of print.
Abstract
Rationale: In heart failure (HF), impaired sarcoplasmic reticulum (SR) Ca2+ release and cytosolic Na+ overload depress mitochondrial Ca2+ (mCa2+) signaling, resulting in a diminished ability to maintain matrix NAD(P)H redox potential, leading to increased oxidative stress when workload increases. Enhancing mCa2+ can reverse this defect but could potentially increase the likelihood of mitochondrial Ca2+ overload.
Objective: To determine if moderate mitochondrial Ca2+ uniporter (MCU) overexpression has beneficial or detrimental effects on the development of HF and incident arrythmias in a guinea pig model (ACi) of HF and sudden cardiac death.
Methods and Results: In vivo viral gene transfer was used to increase MCU levels by ~30% in ACi hearts. Left ventricular myocytes from hearts with MCU overexpression (ACi+MCU) displayed enhanced mCa2+ uptake, decreased oxidative stress, and increased β-adrenergic- and frequency-dependent augmentation of Ca2+ transients and contractions, compared to myocytes from ACi hearts. MCU overexpression decreased SR Ca2+ leak in the ACi group and mitigated the elevated ryanodine receptor disulfide crosslinks in HF. β-adrenergic responses were blunted in isolated perfused ACi hearts and these deficiencies were normalized in ACI+MCU hearts. To examine the in vivo effects of MCU overexpression, ACi hearts were transduced with the MCU virus 2 3w after aortic constriction, at the onset of cardiac decompensation. Two weeks later, cardiac function worsened in the untreated ACi group (fractional shortening: 39{plus minus}1% at 2w and 32{plus minus}1% at 4w), whereas MCU overexpression significantly improved cardiac function (36{plus minus}1% at 2w and 42{plus minus}2% at 4w). MCU overexpression in the decompensating ACi heart also attenuated pulmonary edema and interstitial fibrosis and prevented triggered arrhythmias.
Conclusions: Moderate MCU overexpression in failing hearts enhances contractility and responses to β-adrenergic stimulation in isolated myocytes and perfused hearts by inhibiting mitochondrial oxidative stress-induced SR Ca2+ leak. MCU overexpression also reversed HF and inhibited ectopic ventricular arrhythmias.
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