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Mitochondrial proteome remodeling in ischemic heart failure.

ABSTRACT: Mitochondrial dysfunction is an important part of the decline in cardiac function in heart failure. We hypothesized for hypothesized that there would be specific abnormalities in mitochondrial function and proteome with the progression of ischemic heart failure (HF).We used a high left anterior descending artery (LAD) ligation in 3-4month old male rats to generate HF. Rats were studied 9weeks post-ligation.Electron microscopy of left ventricle samples showed mitochondrial changes including decreased size, increased number, abnormal distribution, and cristae loss. Mitochondria in ischemic HF exhibited decreased total ATP, impaired mitochondrial respiration, as well as reduced complex I activity. Analysis of LV mitochondrial proteins by mass spectrometry was performed, and 31 differentially expressed proteins (p<0.05) of more than 500 total proteins were identified. Of these proteins, 15 were up-regulated and 16 were down-regulated in the failing heart. A set of complex I proteins was significantly decreased, consistent with the impairment of complex I activity. There were distinct changes in mitochondrial function and proteome in ischemic HF. Although there were similarities, the distinction between the reported proteomic changed with TAC pressure overload induced HF and ischemic HF in the current study suggested different pathological mechanisms.Specific changes in mitochondrial protein expression, which correlate with changes in mitochondrial function, have been identified in ischemic HF for the first time.

SUBMITTER: Liu T

PROVIDER: S-EPMC4075482 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Mitochondrial proteome remodeling in ischemic heart failure.

Liu Tingting T Chen Le L Kim Eunjung E Tran Diana D Phinney Brett S BS Knowlton Anne A AA

Life sciences 20140216 1-2

<h4>Aims</h4>Mitochondrial dysfunction is an important part of the decline in cardiac function in heart failure. We hypothesized for hypothesized that there would be specific abnormalities in mitochondrial function and proteome with the progression of ischemic heart failure (HF).<h4>Main methods</h4>We used a high left anterior descending artery (LAD) ligation in 3-4month old male rats to generate HF. Rats were studied 9weeks post-ligation.<h4>Key findings</h4>Electron microscopy of left ventric ...[more]

PMID: 24548633

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Project description:RATIONALE:Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been explored. OBJECTIVE:We will test the hypothesis that elevated mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. METHODS AND RESULTS:Using a unique guinea pig model of nonischemic HF that recapitulates important features of human HF, including prolonged QT interval and high incidence of spontaneous arrhythmic SCD, compartment-specific ROS sensors revealed increased mROS in resting and contracting left ventricular myocytes in failing hearts. Importantly, the mitochondrially targeted antioxidant (MitoTEMPO) normalized global cellular ROS. Further, in vivo MitoTEMPO treatment of HF animals prevented and reversed HF, eliminated SCD by decreasing dispersion of repolarization and ventricular arrhythmias, suppressed chronic HF-induced remodeling of the expression proteome, and prevented specific phosphoproteome alterations. Pathway analysis of mROS-sensitive networks indicated that increased mROS in HF disrupts the normal coupling between cytosolic signals and nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling, and action potential repolarization, suggesting new targets for therapeutic intervention. CONCLUSIONS:mROS drive both acute emergent events, such as electrical instability responsible for SCD, and those that mediate chronic HF remodeling, characterized by suppression or altered phosphorylation of metabolic, antioxidant, and ion transport protein networks. In vivo reduction of mROS prevents and reverses electrical instability, SCD, and HF. Our findings support the feasibility of targeting the mitochondria as a potential new therapy for HF and SCD while identifying new mROS-sensitive protein modifications.

Dataset Information

Mitochondrial proteome remodeling in ischemic heart failure.

Publications

Mitochondrial proteome remodeling in ischemic heart failure.

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