Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation-Contraction Coupling.
Jarrod MooreJourdan EwoldtGabriela V da SilvaAlexandre C PereiraKallyandra PadilhaMatthew L LawtonWeiwei LinRaghuveera GoelIvan LuptakValentina PerissiChristine E SeidmanJonathan SeidmanMichael Thomas ChinChristopher ChenAndrew EmiliPublished in: International journal of molecular sciences (2023)
Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.
Keyphrases
- hypertrophic cardiomyopathy
- left ventricular
- oxidative stress
- young adults
- single cell
- induced apoptosis
- high glucose
- endothelial cells
- diabetic rats
- room temperature
- healthcare
- signaling pathway
- cell cycle arrest
- skeletal muscle
- smooth muscle
- heart failure
- energy transfer
- induced pluripotent stem cells
- drug induced
- atrial fibrillation
- cell death