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.
Highlights
Severe, chronic, isolated mitral regurgitation (MR) is characterized by progressive dilation of the left ventricle (LV) due to significant volume overload.Severe MR leads to a considerate remodeling of cardiac pathology including chamber dilation, cardiac fibrosis, and cardiomyocyte hypertrophy and apoptosis
The expression of myocardial contractile elements such asMYBPC3 and MUbYiHqu11itidnecrreeqauseirdesinawctoirvsaetnioinng-bLyVFU, sAuEg-gEe1stibnegfothreat lciognattrioanctilteoelseumbsetnrtasteofpLrVotmeiynosc, ywtehsimchayabree rceocmogpnroizmediseadndanddegurnaddeerdlibeywporrosteenaisnogmLeVs.fTuhnecrtieofonraef,twereMmVearseupraeidr. tThheeecxiprcroessspiolontloefvbelioo-ffuUnActEio-En1s ianntdhethHeiLr-1cocrerlelsspuosnindginagUgbeinqeusitsinigHniufimcaanntlEyLaISltAereKditi2n4-whoarfsteenr ipnlga-sLmViFd atrraensshfeocwtinoni.nTShuepepxlpermesesniotanl oFfigUurAe ES-4E. 1 was significantly upregulated in HL-1 cardiomyocytes transfected with plasmids containing Ubiquitin-specific protease 15 (USP15), PSMD7, UBE2D1, DNAJC15, and DNAJC8 compared with pcDNA3.1, suggesting that transfection with plasmid containing ubiquitination-related genes would significantly activate protein ubiquitination activity (Figure 4A)
Since microarray identified genes related to the protein ubiquitination pathway to be upregulated in worsening-LVF compared to preserved-LVF, we further evaluated the effects of these genes in cardiomyocytes
Summary
Chronic, isolated mitral regurgitation (MR) is characterized by progressive dilation of the left ventricle (LV) due to significant volume overload.Severe MR leads to a considerate remodeling of cardiac pathology including chamber dilation, cardiac fibrosis, and cardiomyocyte hypertrophy and apoptosis. Patients with severe chronic, isolated MR who received MV repair before LV EF declined, presented progressive LV dilation and worsening of LV EF after the surgery [4] It remains unclear when asymptomatic patients with severe MR with preserved LV EF should undergo surgical intervention [5]. Unveiling the mechanisms underlying MR-causing irreversible LV function deterioration would improve the management of MR-related heart failure and help avoid early but unnecessary MR repair in asymptomatic patients. It remains challenging to extend the survival of the patients with heart failure after surgical correction of the underlying cardiac disease It may belie an incomplete understanding of heterogeneous mechanisms of heart failure due to diverse etiologies, including severe MR-related volume overload, and could be a barrier to a more precise treatment. We revealed differential gene expression profiles in LV from patients with severe MR, with and without progressive LV remodeling after MV repair
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