Abstract
To determine whether up-regulation of miR-1183 targeting the gene for anti-apoptotic factor, B-cell lymphoma 2 (BCL-2) contributes to apoptosis in patients with rheumatic heart disease (RHD). Peripheral blood samples were isolated for miR-1183 characterization. The function of miRNA-1183 in RHD using miRNA mimic on PBMCs and THP-1 cell models. The binding of miR-1183 and Bcl-2 gene was confirmed by luciferase activity test. We also measured expression levels of BCL-2 in heart valve tissue from patients with RHD using ELISA and immunohistochemistry. In silico analysis and reporter gene assays indicated that miR-1183 directly targets the mRNA encoding BCL-2. It is found that miR-1183 binds directly to the 3′UTR of the BCL-2 mRNA and down-regulates the mRNA and protein levels of BCL-2. Overexpression of miR-1183 in RHD patients and cell lines down-regulated BCL-2 expression and induced apoptosis. With the progression of the disease, the expression of BCL-2 in the heart valve tissue of patients with RHD decreased. MiRNA-1183 is up-regulated in RHD and induces cardiac myocyte apoptosis through direct targeting and suppression of BCL-2, both of which might play important roles in RHD pathogenesis. During the compensatory period of RHD, up-regulated miR-1183 destroyed the balance of apoptosis proteins (Bax and BAK) in Bcl-2 family, enhance the apoptosis cascade reaction and reduce the anti apoptosis effect. The significantly higher expression levels of miR-1183 appear to play distinct roles in RHD pathogenesis by regulation BCL-2, possibly affecting myocardial apoptosis and remodeling in the context of RHD.
Highlights
Rheumatic heart disease (RHD) is an autoimmune disease induced by group A hemolytic streptococcus infections, primarily affecting people under 40 years old, and often damaging endocardium, pericardium, and myocardium [1,2]
On the basis of our previous work, we used the GeneChip® miRNA Array to profile the quantitative change of miRNAs in plasma of 1, 2, N3 and 4, 5, 6 RHD patients, differently expressed miRNAs were screened on the chip (Table 2)
In the detected the expression level of miR-1183 using qPCR, MiR-1183 is up-regulated in the blood samples from RHD patients; the Bcl-2 mRNA was significantly down-regulated in RHD cases compared with the healthy normal control samples
Summary
Rheumatic heart disease (RHD) is an autoimmune disease induced by group A hemolytic streptococcus infections, primarily affecting people under 40 years old, and often damaging endocardium, pericardium, and myocardium [1,2]. Streptococcus cross-reactions act on heart tissue, driving CD4+ T cells to expand and produce autoimmune damage, which is considered to be the most likely pathogenesis of RHD [4,5]. Rheumatic carditis can involve the endocardium, myocardium, and pericardium It can occur repeatedly and acutely during the course of the disease, causing valve congestion, swelling, fibrosis, and adhesion of tendon papillary muscle. All these effects produce permanent pathological changes in the myocardium after becoming chronic, which is a characteristic feature of heart failure in RHD patients [6].
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