Ubiquitin Pathway Is Associated with Worsening Left Ventricle Function after Mitral Valve Repair: A Global Gene Expression Study.

• 影响指数: 6.208
• 发表时间: Jul 2020 18
• 来源期刊: Int J Mol Sci
• DOI: 10.3390/ijms21145073
• PMID: 32708358
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 生物
• 作者列表: Tsai FC,Chang GJ,Lai YJ,Chang SH,Chen WJ,Yeh YH

关键词: heart failure; mitral valve; ubiquitin; volume overload

Mesh: Actins / metabolism; Adult; Aged; Apoptosis / genetics; Bone Morphogenetic Protein Receptors / genetics metabolism; Cell Line; Cell Survival / genetics; Female; Gene Expression Regulation / genetics; Heart Failure / genetics metabolism; Heart Ventricles / physiopathology; Humans; Male; Middle Aged; Mitral Valve / enzymology metabolism surgery; Mitral Valve Insufficiency / enzymology genetics metabolism physiopathology; Myocytes, Cardiac / metabolism; Oligonucleotide Array Sequence Analysis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics metabolism; Ribosomal Protein S6 Kinases, 70-kDa / genetics metabolism; Signal Transduction / genetics; Ubiquitin / genetics metabolism; Ubiquitin-Activating Enzymes / genetics metabolism; Ubiquitination / genetics; Ventricular Function, Left / genetics; X-Linked Inhibitor of Apoptosis Protein / genetics metabolism

Abstract

The molecular mechanism for worsening left ventricular (LV) function after mitral valve (MV) repair for chronic mitral regurgitation remains unknown. We wished to assess the LV transcriptome and identify determinants associated with worsening LV function post-MV repair. A total of 13 patients who underwent MV repair for chronic primary mitral regurgitation were divided into two groups, preserved LV function (N = 8) and worsening LV function (N = 5), for the study. Specimens of LV from the patients taken during surgery were used for the gene microarray study. Cardiomyocyte cell line HL-1 cells were transfected with gene-containing plasmids and further evaluated for mRNA and protein expression, apoptosis, and contractile protein degradation. Of 67,258 expressed sequence tags, microarrays identified 718 genes to be differentially expressed between preserved-LVF and worsening-LVF, including genes related to the protein ubiquitination pathway, bone morphogenetic protein (BMP) receptors, and regulation of eIF4 and p70S6K signaling. In addition, worsening-LVF was associated with altered expressions of genes pathologically relevant to heart failure, such asdownregulated apelin receptors and upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). HL-1 cardiomyocyte cells transfected with ubiquitination-related genes demonstrated activation of the protein ubiquitination pathwaywith an increase in the ubiquitin activating enzyme E1 (UAE-E1). It also led to increased apoptosis, downregulated and ubiquitinated X-linked inhibitor of apoptosis protein (XIAP), and reduced cell viability. Overexpression of ubiquitination-related genes also resulted in degradation and increased ubiquitination of α-smooth muscle actin (SMA). In conclusion, worsening-LVF presented differential gene expression profiles from preserved-LVF after MV repair. Upregulation of protein ubiquitination-related genes associated with worsening-LVF after MV repair may exert adverse effects on LV through increased apoptosis and contractile protein degradation.