The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts

Abstract

Fibrosis accompanies most heart diseases and is associated with adverse patient outcomes. Transforming growth factor (TGF)β drives extracellular matrix remodelling and fibrosis in the failing heart. Some members of the ADAMTSL (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs-like) family of secreted glycoproteins bind to matrix microfibrils, and although their function in the heart remains largely unknown, they are suggested to regulate TGFβ activity. The aims of this study were to determine ADAMTSL2 levels in failing hearts, and to elucidate the role of ADAMTSL2 in fibrosis using cultured human cardiac fibroblasts (CFBs). Cardiac ADAMTSL2 mRNA was robustly increased in human and experimental heart failure, and mainly expressed by fibroblasts. Over-expression and treatment with extracellular ADAMTSL2 in human CFBs led to reduced TGFβ production and signalling. Increased ADAMTSL2 attenuated myofibroblast differentiation, with reduced expression of the signature molecules α-smooth muscle actin and osteopontin. Finally, ADAMTSL2 mitigated the pro-fibrotic CFB phenotypes, proliferation, migration and contractility. In conclusion, the extracellular matrix-localized glycoprotein ADAMTSL2 was upregulated in fibrotic and failing hearts of patients and mice. We identified ADAMTSL2 as a negative regulator of TGFβ in human cardiac fibroblasts, inhibiting myofibroblast differentiation and pro-fibrotic properties.

The Transcriptional Landscapes and Key Genes in Brain Arteriovenous Malformation Progression in a Venous Hypertension Rat Model Revealed by RNA Sequencing

“… 25 The increasing expressions of Adamtsl2 in heart disease were also observed. 26 , 27 SPON2 belongs to the F-spondin family of secreted extracellular matrix proteins, and act as pattern recognition receptors to regulate immunity. The transcriptional activation of SPON2 can promote macrophage chemotaxis ability in vascular endothelial cells, and the endothelial derived chemoattractive cue for macrophage migration can be suppressed after SPON2 deletion.…”

Research Article The small leucine-rich proteoglycan fibromodulin exerts anti-fibrotic effects in cultured human cardiac fibroblasts

“…hfCFBs and haCFBs. While CFBs from adult hearts are more relevant to human patients, the fetal CFBs constitute an important research tool as they express a more mature ECM in culture, including the TGFβ signaling system, which is considered hard to study in cultured cells (Kapur et al, 2007;Peng et al, 2010;Rypdal et al, 2021).…”

“…CFBs isolated from ventricles of a human adult heart (C-12375, PromoCell) and a human fetal heart (306-05F, Sigma-Aldrich), haCFbs and hfCFBs, respectively, were used. Of note, hfCFBs are known to produce a more mature ECM in culture than adult CFBs including structural fibrils and the TGF system (Kapur et al, 2007;Peng et al, 2010;Rypdal et al, 2021), while CFBs from the adult human heart are more relevant to heart failure patients. Both haCFBs and hfCFBs followed the same protocol for defreezing, seeding, passaging, stimulation and transduction, but with use of different reagents clarified below.…”

ADAMTS Proteins and Vascular Remodeling in Aortic Aneurysms

“…In heart ventricles undergoing heart fibrosis due to heart failure, all ADAMTSLs mRNA were overexpressed except ADAMTSL6 . ADAMTSL2 was the most upregulated in cardiac fibroblasts [ 76 ]. This increase resulted in reduced TGFβ production and signaling pathway activation.…”