Here, we examine key regulatory pathways underlying the transition from compensated hypertrophy (HYP) to decompensated heart failure (HF) and sudden cardiac death (SCD) in a guinea pig pressure-overload model by integrated multiome analysis. Relative protein abundances from sham-operated HYP and HF hearts were assessed by iTRAQ LC–MS/MS. Metabolites were quantified by LC–MS/MS or GC–MS. Transcriptome profiles were obtained using mRNA microarrays. The guinea pig HF proteome exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction, fibrosis, inflammation, and extravasation. Fatty acid metabolism, mitochondrial transcription/translation factors, antioxidant enzymes, and other mitochondrial procsses, were downregulated in HF but not HYP. Proteins upregulated in HF implicate extracellular matrix remodeling, cytoskeletal remodeling, and acute phase inflammation markers. Among metabolites, acylcarnitines were downregulated in HYP and fatty acids accumulated in HF. The correlation of transcript and protein changes in HF was weak (R2 = 0.23), suggesting post-transcriptional gene regulation in HF. Proteome/metabolome integration indicated metabolic bottlenecks in fatty acyl-CoA processing by carnitine palmitoyl transferase (CPT1B) as well as TCA cycle inhibition. On the basis of these findings, we present a model of cardiac decompensation involving impaired nuclear integration of Ca2+ and cyclic nucleotide signals that are coupled to mitochondrial metabolic and antioxidant defects through the CREB/PGC1α transcriptional axis.
Rationale: In heart failure (HF), impaired sarcoplasmic reticulum (SR) Ca 2+ release and cytosolic Na + overload depress mitochondrial Ca 2+ (mCa 2+ ) signaling, resulting in a diminished ability to maintain matrix NAD(P)H redox potential, leading to increased oxidative stress when workload increases. Enhancing mCa 2+ can reverse this defect but could potentially increase the likelihood of mitochondrial Ca 2+ overload. Objective: To determine if moderate mitochondrial Ca 2+ 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 mCa 2+ uptake, decreased oxidative stress, and increased β‐adrenergic- and frequency-dependent augmentation of Ca 2+ transients and contractions, compared to myocytes from ACi hearts. MCU overexpression decreased SR Ca 2+ 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 Ca 2+ leak. MCU overexpression also reversed HF and inhibited ectopic ventricular arrhythmias.
Cardiac all-trans retinoic acid decreases in heart failure despite adequate retinol reserves.
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