LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy

Abstract

Aim Dilated cardiomyopathy (DCM) is characterised by left ventricular dilation and associated with systolic dysfunction. Recent evidence has reported the high expression of latent transforming growth factor beta binding protein 2 (LTBP2) in heart diseases, which may play a role in regulating multiple biological functions of myocardial cells. Thus, this study set out to investigate the molecular mechanism and effects of LTBP2 in myocardial oxidative stress injury, fibrosis and remodelling in a rat model of DCM, with the involvement of NF‐κB signalling pathway. Methods The rat model of DCM was treated with si‐LTBP2 and/or activator of NF‐κB signalling pathway to examine the haemodynamic indexes, cardiac functions, oxidative stress injury, fibrosis and remodelling. Moreover, in vitro experiments were conducted to verify the regulatory role of LTBP2 and NF‐κB signalling pathway in DCM. Results LTBP2 was up‐regulated in DCM rats. After LTBP2 was knocked down, haemodynamic indexes, HW/BW ratio, collagen volume fraction (CVF) level, positive expression of LTBP2, levels of reactive oxygen species (ROS), malondialdehyde (MDA), interleukin‐6 (IL‐6), tumour necrosis factor‐alpha (TNF‐α), tumour necrosis factor beta 1 (TGF‐β1) and brain natriuretic peptide (BNP) were all decreased. Meanwhile, levels of LTBP2, Col‐I, Col‐III, p65 and p52 were also reduced, while HW, BW and levels of SOD and TAOC were increased. In contrast, activation of NF‐κB signalling pathway reversed effects of LTBP2 gene silencing. These findings were confirmed by in vivo experiments. Conclusions LTBP2 silencing can attenuate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling in DCM rats by down‐regulating the NF‐κB signalling pathway.

Integrated microarray analysis to identify potential biomarkers and therapeutic targets in dilated cardiomyopathy

“…The DOX mouse model also exhibits progressive cardiac functional decline and ventricular dilation (29), which is consistent with the diagnosis of dcM. In addition, while the specific pathogenesis of DCM and the mechanism of its progressive progression remain unknown, previous studies revealed that the development of dcM may be associated with decreased mitochondrial function (56), abnormal oxidative stress (57,58), as well as excessive myocardial apoptosis and necrosis (59,60). In line with these possible causes, it has also been reported that the DOX model is accompanied by similar mitochondrial dysfunction (29,61), oxidative stress injury (62) and apoptotic changes (63).…”

Dissecting the Cellular Landscape and Transcriptome Network in Viral Myocarditis by Single-Cell RNA Sequencing

“…We noted three genes, Postn (periostin), Ltbp2 (latent TGF-β binding protein 2), and Thbs4 of interest in cluster 5. While Postn, an ECM protein, is critical for tissue development and regeneration and plays a role in wound healing and ventricular remodeling in myocardial events 41 , Ltbp2 and Thbs4 have roles in myocardial fibrosis in DCM 42 or the fibrotic process 43 . Similarly, three transcripts, Apoe , Tgfbi, and Mfap4, were found interesting in cluster 6.…”

“…Our scRNAseq analysis revealed 12 distinct clusters that express overlapping genes ( Fig 4A, B, C ). Several of these ( Wif1a, Npy ) 47 have been previously shown to be involved in wound healing, ventricular/cardiac remodeling, and myocardial fibrosis in DCM pathogenesis ( Ltbp2 , Thbs4 and Tgfbi ) 24, 42, 43 . However, a subset of genes ( Mt1, Mt2, Cxcl1 ) 25, 30 that have immune modulatory roles and promote angiogenesis ( Vegfd ) were also detected in various clusters.…”

Cardiomyopathies in China: A 2018–2019 state‐of‐the‐art review

“…An in vivo study investigated the role of LTBP2 in these processes. 11 Lamin A/C ( LMNA ) mutation causes not only DCM but also heart block. The mechanism underlying LMNA nonsense mutation-induced cardiac conduction defects through atrioventricular (AV) node fibrosis is upregulated extracellular cellular matrix gene expression upon activation of cardiac apoptosis; this explains heart block in LMNA mutation-carrying DCM patients.…”