Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease

Abstract

Rheumatic heart disease (RHd) affects numerous individuals annually; however, its pathogenesis remains unclear. The sphingosine 1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription 3 (STAT3) have recently been shown to be involved in valvular damage via the promotion of the differentiation of T helper 17 (Th17) cells during the development of RHd-induced valvular damage. The present study investigated whether altering the expression of S1PR1 or STAT3 attenuates valvular damage due to RHd. Inactivated group A streptococcus (GAS) was used to establish a rat model of RHd. Recombinant adeno-associated viral vectors carrying an S1PR1 overexpression sequence were used to overexpress S1PR1. STAT3 small interfering RNA (STAT3-siRNA) was used to inhibit STAT3 expression. Reverse transcription-quantitative PcR (RT-qPcR) was performed to detect the mRNA expression of S1PR1, STAT3, collagen type III α1 chain (Col3a1) and fibroblast-specific protein 1. Western blotting (WB) and immunohistochemistry were used to detect the levels of S1PR1, STAT3, phosphorylated (p-) STAT3, and retinoic acid-related orphan receptor γT (RORγt) proteins. Enzyme-linked immunosorbent assays (ELISAs) and immunohistochemistry were used to detect the levels of interleukin (IL)-6 and IL-17. Hematoxylin and eosin (H&E) staining and Sirius Red staining were performed to evaluate the degree of inflammation and fibrosis in the valvular tissues. S1PR1 expression was decreased in the valvular tissues of the rats with RHd. The levels of IL-6, IL-17 and p-STAT3 in the rats with RHD were increased. The degree of valvular inflammation and fibrosis in the rats with RHD was also increased. The overexpression of S1PR1 and the inhibition of STAT3 reduced the total p-STAT3 level, resulting in decreased levels of IL-6, IL-17 and RORγt, and a reduced degree of valvular inflammation and fibrosis. These results suggest that the expression of S1PR1 and STAT3 may be involved in valvular tissue damage due to RHd. Thus, strategies designed to interfere with the expression of S1PR1 or STAT3 may affect the expression of Th17 cell-related cytokines and may thus attenuate valvular damage due to RHd.

Potential Involvement of M1 Macrophage and VLA4/VCAM-1 Pathway in the Valvular Damage Due to Rheumatic Heart Disease

“…Previous studies have also reported infiltration of CD4 + lymphocytes into the neovascularization area of RHD valves [47]. Furthermore, our previous studies and those of others have shown a close relationship between valvular damage and Th17 cells that differentiated from CD4 + T cells [15,40,48]. Th17 cells that differentiated from CD4 + T cells are the key factors during the pathogenesis of RHD [49].…”

“…The classical method was used to establish the RHD rat model [14,[37][38][39][40] over a period of 9 weeks. At the beginning of the experiment, rats in the RHD group were treated with unilateral rear footpad injections of a 1:1 (v/v) mixed solution of 0.1 mL of antigen and CFA.…”

LINC00707 impairs the Natural Killer cell antitumour activity in hepatocellular carcinoma through decreasing YTHDF2 stability

“…In the context of autoimmune diseases, its suppression aligns with protective mechanisms against myocardial injury, particularly through the inhibition of miR‐23 22 . The dynamic interplay between LINC00707, microRNAs and target genes underscores its potential as a therapeutic target in various pathological conditions 23,24 . Although some investigations have shed light on the role of LINC00707 in HCC, 12,13 there remains a substantial gap in our understanding.…”

“… 22 The dynamic interplay between LINC00707, microRNAs and target genes underscores its potential as a therapeutic target in various pathological conditions. 23 , 24 Although some investigations have shed light on the role of LINC00707 in HCC, 12 , 13 there remains a substantial gap in our understanding. As a result, this investigation validated the oncogenic role of LINC00707 in HCC through assessments like cell colony assays, transwell migration and transwell invasion assays.…”

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

“…Its conjugate GDCA upregulates ZBP1 in macrophages promoting necroptosis and accelerated fibrosis in a BDL model with relevance for EHBA 64 . Importantly, activation of S1PR by its endogenous ligand sphingosine 1 is linked to STAT3 activation in Tregs, their infiltration into tumor tissue 65 , and Th17/Treg balance in rheumatic heart disease and aplastic anemia 66, 67 .…”