Tanshinone IIA promotes the apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis by up-regulating lncRNA GAS5

Abstract

Rheumatoid arthritis (RA) is a common chronic autoimmune joint disease characteristic of elevated proliferation and infiltration of fibroblast-like synoviocytes (FLS). Here, we aimed to explore the mechanisms of the Tanshinone IIA (Tan IIA)-induced apoptosis of FLS from patients with RA (termed RAFLS). Cell Counting Kit-8 (CCK-8) assay and Annexin V staining revealed that RAFLS viability decreased and apoptosis increased after Tan IIA treatment. Long non-coding RNA (lncRNA) GAS5 expression was significantly decreased in the synovial tissues and RAFLS, while Tan IIA treatment resulted in an up-regulation of GAS5. Consistently, knockdown of GAS5 using siRNA inhibited RAFLS apoptosis. Mechanistically, GAS5 knockdown down-regulated the expression of cleaved caspase-3 and caspase-9 in the RAFLS cells and activated the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. These data indicate that Tan IIA promotes RAFLS apoptosis by up-regulating lncRNA GAS5, with enhanced expression of cleaved caspase-3/caspase-9 and inhibited PI3K/AKT signaling.

Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis

“…In 2011, Zhang et al found that Genistein (34) (50, 100, and 200 µM) can induce apoptosis in vitro cultured FLS of CIA rats, and the mechanism regulates the expression of apoptosis-related proteins Bax and Bcl-2 by inhibiting Akt expression [131]. Another study by Li et al reported that Tanshinone IIA (12, 40 µM) can promote apoptosis in RA-FLS via up-regulating lncRNA GAS5, cleaved Caspase-3 and -9 and inhibiting PI3K/Akt signaling [132]. In addition, Yang studied the effect of Anacardic acid (35) on RA, and found that anacardic acid has good therapeutic effect on symptoms of CIA rats, and the Anacardic acid (5, 30, and 60 µM) can induce apoptosis of the RA-FLS, and the possible mechanism is closely related to the PI3K/Akt signal pathway [133].…”

Therapeutic potential of extracellular vesicle‐associated long noncoding RNA

“…36 Li et al showed that the phytochemical Tanshinone IIA was able to promote the apoptosis of these fibroblast-like synoviocytes by upregulating lncRNA GAS5. 41 Another study by Zhang et al utilized LPS-induced chondrocytes and showed that lncRNA HOTAIR inactivated NF-κB signaling by downregulating miR-138. In rheumatoid arthritis animal models, it was found that chondrocyte proliferation was upregulated and inflammatory markers IL-17 AND IL-23 were downregulated by HOTAIR.…”

“…Rheumatoid arthritis is characterized by invasive fibroblast‐like synoviocytes that cause joint destruction 36 . Li et al showed that the phytochemical Tanshinone IIA was able to promote the apoptosis of these fibroblast‐like synoviocytes by upregulating lncRNA GAS5 41 . Another study by Zhang et al utilized LPS‐induced chondrocytes and showed that lncRNA HOTAIR inactivated NF‐κB signaling by downregulating miR‐138.…”

Involvement of long noncoding RNAs in the pathogenesis of autoimmune diseases

“…Several lncRNAs, including MALAT1 [ 80 ], UCA1 [ 81 ], DILC [ 82 ], LncIL7R [ 83 ] and LINC00152 [ 84 ], have been reported to contribute to apoptosis and proliferation in RA-FLSs. lncRNA GAS5 [ 85 , 86 ] and ITSN1-2 [ 87 ] are implicated in apoptosis and inflammation in RA FLSs. MEG3, a lncRNA that participates in cell proliferation in cancer tissues, also modulates inflammation by targeting NLRC5 [ 88 ], miR-141 and the AKT/mTOR pathway [ 89 ].…”

“… [ 82 ] Lnc-IL7R Human FLS – Promotes growth of RA FLS through interaction with EZH2 [ 83 ] LINC00152 Human FLS Up-regulated Regulates proliferation and apoptosis via Wnt/beta-catenin signaling pathway [ 84 ] GAS5 Human Tanshinone IIA -treated FLS, plasma Down-regulated Responsible for apoptosis and IL-18 expression. [ 85 , 86 ] ITSN1-2 Human FLS Up-regulated Regulates apoptosis, proliferation and inflammation by NOD2/RIP2 pathway. [ 87 ] PVT1 Rat FLS Up-regulated Regulates inflammation response and apoptosis.…”