Proteomic profiling of human myocardium revealed dysregulation of Ras-MAPK, ubiquitin-mediated proteolysis, angiogenesis-related, and Hippo pathways in hypertrophic cardiomyopathy.
Case-Control (n=114)
Yes
What signaling pathways are differentially regulated in the human myocardium of patients with hypertrophic cardiomyopathy compared to nonfailing hearts?
Comprehensive proteomic profiling of human HCM myocardium identifies dysregulation in both novel (e.g., Ras-MAPK, Hippo) and known pathways associated with disease pathogenesis and severity.
BACKGROUND Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown. OBJECTIVES The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling. METHODS In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate 7,000 proteins) and largest-scale (n = 99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras–mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM.
“Current therapeutics for HCM are not as effective as we would wish because we haven't cracked the black box – the molecular target – that we need therapies to reach. Moreover, the signaling pathways that control the progression of HCM from mild to severe disease are largely unknown.”
Lumish et al. (Wed,) 在 Hypertrophic cardiomyopathy (n=114) 中开展了一项病例对照研究。在 Differentially expressed proteins and signaling pathways 方面对 Hypertrophic cardiomyopathy 与 Nonfailing hearts 进行了评估。人类心肌的蛋白质组学分析揭示了 Ras-MAPK、泛素介导的蛋白水解、血管生成相关以及 Hippo 通路在肥厚型心肌病中的失调。