miR-29a-3p/THBS2 Axis Regulates PAH-Induced Cardiac Fibrosis

Abstract

Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.

Identification and validation of mutual hub genes in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated usual interstitial pneumonia

“…The THBS2 protein has a substantial role in facilitating the proliferation, migration, and invasion of tumor cells [ 29 ]. It has also been reported highly associated with organ fibrosis, such as cardiac, liver, and kidney fibrosis, for it participates in the formation and repair of ECM [ [30] , [31] , [32] ]. Furthermore, THBS2 had previously been discovered upregulated in IPF patients, but it was rarely studied in the pathogenesis of pulmonary fibrosis [ 33 ].…”

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

“…39,40 In the context of cardiac fibrosis, miR-29a-3p exerts its anti-fibrotic effect by targeting and inhibiting THBS2 expression. 41 Moreover, transcriptomic analyses have identified THBS2 as a potential biomarker for nonalcoholic steatohepatitis and advanced liver fibrosis. 42 Deep learning CNN was employed for model construction and validation, demonstrating stability and accuracy with the ROCs of the training set (AUC = 0.853) and validation set (AUC = 1.000).…”

“… 39 , 40 In the context of cardiac fibrosis, miR‐29a‐3p exerts its anti‐fibrotic effect by targeting and inhibiting THBS2 expression. 41 Moreover, transcriptomic analyses have identified THBS2 as a potential biomarker for non‐alcoholic steatohepatitis and advanced liver fibrosis. 42 …”

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

“…The expression of CCL18 [109], SLAMF7 [110], GPR174 [111], CCR4 [112], POU4F2 [113]. CCR2 [114], IL2RB [115], CCL4 [116], CCL24 [117], FASLG (Fas ligand) [118], CD24 [119], TDGF1 [120], CD28 [121], IL7R [122], CYP11B1 [123], CCL5 [124], CCL3 [125], LTF (lactotransferrin) [126], GPNMB (glycoprotein nmb) [127], CD209 [128], IL2RG [129], CHIT1 [130], TAB2 [131], CD163 [132], ALOX15B [133], NMRK2 [134], HGF (hepatocyte growth factor) [135], TRPM8 [136], DIO3 [137], SIGLEC1 [138], TTR (transthyretin) [139], IL24 [140], F13A1 [141], IL9 [142], VEGFA (vascular endothelial growth factor A) [143], RASAL1 [144], ADM (adrenomedullin) [145], ANGPTL4 [146], CHI3L1 [147], LDB3 [148], CNP (2’,3’-cyclic nucleotide 3’ phosphodiesterase) [149], HES6 [150], CMTM5 [151], PLXNB3 [152], KLK8 [153], CDKN1C [154], INSIG1 [155], GREM1 [156], ATF3 [157], HK2 [158], MCAM (melanoma cell adhesion molecule) [159], SEMA4D [160], GLUL (glutamate-ammonia ligase) [161], S1PR5 [162], FN3K [163], MEIS1 [164], ADAMTS4 [165], BIN1 [166], BMP2 [167], LMNA (lamin A/C) [168], ERBB3 [169], DLL1 [170], THBS2 [171], GADD45B [172], MYH6 [173]. PNPLA3 [174], ACTN2 [175], MMP15 [176], SVEP1 [177], CPB2 [178], DYSF (dysferlin) [179], ADAMTSL2 [180], NINJ2 [181], LRP2 [106], PHLDA3 […”