背景:肥厚型心肌病(HCM)是一种常见的遗传性心脏病。患有HCM的女性往往发病较晚,但病程更严重。然而,这些差异的潜在病理生物学机制仍然未知.
方法:本研究包括97例有症状的阻塞性HCM患者(53例男性/44例女性)和23例对照心脏组织的心肌切除术样本。对所有样品进行RNA测序。对代表性的样品子集进行基于质谱的蛋白质组学和磷酸蛋白质组学。
结果:转录组,蛋白质组,两性之间的磷酸蛋白质组相似,并且在PCA绘图中没有分离。总的来说,对照女性和对照男性之间有482个差异表达基因(DEGs),而HCM女性和HCM男性之间只有53个DEGs。HCM女性和对照女性之间的DEG为1983,而HCM男性和对照男性之间的DEG为1064。此外,在HCM女性和HCM男性中,肥大通路的转录下调增加。与对照雌性相比,HCM雌性具有119种差异表达的蛋白质,而与对照雄性相比,HCM雄性仅具有27种。最后,磷酸蛋白质组显示,与对照组相比,雌性有341种差异磷酸化蛋白(DPP),而雄性只有184种.有趣的是,女性的肥大通路存在低磷酸化和失活,而男性的过度磷酸化和活化。
结论:有微妙的,但在HCM的多组学中存在生物学相关的差异。这项研究提供了转录组中性别特异性差异的最全面的图谱,蛋白质组,和磷酸化蛋白质组存在于手术子宫切除术治疗梗阻性HCM时。
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown.
METHODS: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples.
RESULTS: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1983 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males.
CONCLUSIONS: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM.