The long noncoding RNA THBS1-AS1 promotes cardiac fibroblast activation in cardiac fibrosis by regulating TGFBR1

Abstract

Cardiac fibrosis is associated with an adverse prognosis in cardiovascular disease, which results in a decreased cardiac compliance and ultimately heart failure. Recent studies have identified the role of long non-coding RNA (lncRNA) in cardiac fibrosis. However, the functions of many lncRNAs in cardiac fibrosis remain to be characterized. Through a whole-transcriptome sequencing and bioinformatics analysis on a mouse model of pressure overload-induced cardiac fibrosis, we screened a key lncRNA termed thrombospondin 1 antisense 1 (THBS1-AS1), which was positively associated with cardiac fibrosis. In vitro functional studies demonstrated that the silencing of THBS1-AS1 ameliorated TGF-β1 effects on cardiac fibroblasts (CFs) activation and the overexpression of THBS1-AS1 displayed the opposite effect. A mechanistic study revealed that THBS1-AS1 could sponge miR-221/222 to regulate the expression of TGFBR1. Moreover, under TGF-β1 stimulation, the forced expression of miR-221/222 or the knockdown TGFBR1 significantly reversed the THBS1-AS1 overexpression induced further cardiac fibroblast activation. In vivo, specific knockdown of THBS1-AS1 in activated cardiac fibroblasts significantly alleviated transverse aorta constriction (TAC)-induced cardiac fibrosis in mice.Finally, we demonstrated that the human THBS1-AS1 can also affect the activation of cardiac fibroblasts by regulating TGFBR1. In conclusion, this study reveals that lncRNA THBS1-AS1 is a novel regulator of cardiac fibrosis and may serve as a potential target for the treatment of cardiac fibrosis.

Pathogenic mycoplasmas of humans regulate the long noncoding RNAs in epithelial cells

“…There are several notable lncRNAs that are affected upon Mg or Mp infection ( Fig. 1 A), such as DIO3OS (maintaining monoallelic expression [ 70 ]), PRKG1-AS1 (muscle aging [ 71 ]), CCN2-AS1 (possible role in acute lymphoblastic leukemia [ 72 ]), THBS1-AS1 (role in cardiac fibrosis [ 73 ]), MIR222HG (castration-resistant prostate cancer [ 74 ]), HDAC2-AS2 (possible role in preeclampsia [ 75 ]), LINC02323 (role in epithelial-mesenchymal transition [ 76 ]) etc.…”

Machine learning and single‐cell transcriptome profiling reveal regulation of fibroblast activation through THBS2/TGFβ1/P‐Smad2/3 signalling pathway in hypertrophic scar

“…THBS1 is highly expressed in fibroblasts specific to systemic sclerosis skin and plays a significant role in cardiac fibrosis. 37,38 THBS2, a significant anti-angiogenic matricellular protein, assumes a crucial role as a regulator of ECM homeostasis during the progression of fibrosis. 39,40 In the context of cardiac fibrosis, miR-29a-3p exerts its anti-fibrotic effect by targeting and inhibiting THBS2 expression.…”

“…Among them, THBS1 and THBS2 have been extensively studied in fibrosis. THBS1 is highly expressed in fibroblasts specific to systemic sclerosis skin and plays a significant role in cardiac fibrosis 37,38 . THBS2, a significant anti‐angiogenic matricellular protein, assumes a crucial role as a regulator of ECM homeostasis during the progression of fibrosis 39,40 .…”

Biomarkers of heart failure: advances in omics studies

“…57 In terms of modulating cardiac fibrosis, lncRNAs like LINC01013 have made strides, being recognized as potential novel regulators influencing the onset and progression of myocardial fibrosis. 58 Additionally, lncRNAs can be implicated in the orchestration of mitochondrial autophagy, thereby influencing the integrity and homeostasis of cardiomyocyte mitochondria. The disorder of lncRNA expression levels is related to cardiopulmonary dysfunction, which may be achieved by regulating the mitophagy pathway.…”