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Characterizing a long-term chronic heart failure model by transcriptomic alterations and monitoring of cardiac remodeling.

ABSTRACT: The long-term characteristics of transcriptomic alterations and cardiac remodeling in chronic heart failure (CHF) induced by myocardial infarction (MI) in mice are not well elucidated. This study aimed to reveal the dynamic changes in the transcriptome and cardiac remodeling in post-MI mice over a long time period. Monitoring C57BL/6 mice with MI for 8 months showed that approximately 44% of mice died of cardiac rupture in the first 2 weeks and others survived to 8 months with left ventricular (LV) aneurysm. The transcriptomic profiling analysis of cardiac tissues showed that the Integrin and WNT pathways were activated at 8 months after MI while the metabolism-related pathways were inversely inhibited. Subsequent differential analysis at 1 and 8 months post-MI revealed significant enrichments in biological processes, including consistent regulation of metabolism-related pathways. Moreover, echocardiographic monitoring showed a progressive increase in LV dimensions and a decrease in the LV fractional shortening during the first 4 weeks, and these parameters progressed at a lower rate till 8 months. A similar trend was found in the invasive LV hemodynamics, cardiac morphological and histological analyses. These results suggested that mouse MI model is ideal for long-term studies, and transcriptomic findings may provide new CHF therapeutic targets.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC8202904 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleDespite 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.ObjectiveWe 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 resultsUsing 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.ConclusionsmROS 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.

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Characterizing a long-term chronic heart failure model by transcriptomic alterations and monitoring of cardiac remodeling.

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