Emerging roles for the ADAMTS-like family of matricellular proteins in cardiovascular disease through regulation of the extracellular microenvironment

Abstract

Dysregulation of the extracellular matrix (ECM) occurs widely across cardiovascular pathologies. Recent work has revealed important roles for the «a disintegrin-like and metalloprotease domain with thrombospondin-type 1 motifs like" (ADAMTSL) family of secreted glycoproteins in cardiovascular tissues during development and disease. Key insights in this regard have come from naturally occurring gene mutations in humans and animals that result in severe diseases with cardiovascular manifestations or aortopathies. Expression of ADAMTSL genes is greatly increased in the myocardium during heart failure. Genetically modified mice recapitulate phenotypes of patients with ADAMTSL mutations and demonstrate important functions in the ECM. The novel functions thus disclosed are intriguing because, while these proteins are neither structural, nor proteases like the related ADAMTS proteases, they appear to act as regulatory, i.e., matricellular proteins. Evidence from genetic variants, genetically engineered mouse mutants, and in vitro investigations have revealed regulatory functions of ADAMTSLs related to fibrillin microfibrils and growth factor signaling. Interestingly, the ability to regulate transforming growth factor (TGF)β signaling may be a shared characteristic of some ADAMTSLs. TGFβ signaling is important in cardiovascular development, health and disease and a central driver of ECM remodeling and cardiac fibrosis. New strategies to target dysregulated TGFβ signaling are warranted in aortopathies and cardiac fibrosis. With their emerging roles in cardiovascular tissues, the ADAMTSL proteins may provide causative genes, diagnostic biomarkers and novel treatment targets in cardiovascular disease. Here, we discuss the relevance of ADAMTSLs to cardiovascular medicine.

Keywords: Aortic aneurysms; Cardiac fibrosis; Extracellular matrix; Growth factor signaling; Heart failure; Microfibrils.

Fig. 1

The ADAMTSL family of secreted glycoproteins is part of the cardiac extracellular matrix (ECM). a) Pathogenic stimuli to the heart, such as inflammatory cytokines, myocardial stretch, or cardiomyocyte death, trigger cardiac fibroblast to myofibroblast differentiation and ECM expansion, resulting in cardiac fibrosis. b) The ADAMTSL protein family members reside in the myocardial ECM, tethered to fibrillin microfibrils and latent TGFβ-binding proteins (LTBPs), and potentially, other ECM macromolecular complexes such as collagen fibrils and basement membranes. c) Domain structure of the seven ADAMTSL family members. They share structural similarity with the ancillary domains of the ADAMTS proteases, illustrated here with the structure of ADAMTS1, but lack protease domains (adapted from Apte SS. J Biol Chem. 2009 [12]). Created with BioRender.com

Fig. 2

The ADAMTSL interactome. The ADAMTSL proteins reside in the cardiovascular extracellular matrix (ECM) where they bind components of the microfibrils (fibrillin-1 and fibrillin-2) and latent TGFβ-binding proteins (LTBPs). The ADAMTSL proteins have known interactions with the ECM-residing enzymes MMPs, LOX and ADAMTS10, and bind heparin, suggesting an interaction with heparan sulfate proteoglycans. A proposed molecular mechanism of ADAMTSLs in the ECM is shown, whereby ADAMTSLs control the activation of TGFβ, and consequent initiation of the canonical TGFβ-SMAD2/3 signaling cascade. TGFβ signaling leads to transcription of genes promoting ECM remodeling and fibrosis. Created with BioRender.com

Fig. 3

Future directions for ADAMTSL proteins as potential genetic substrates, biomarkers, and therapeutic targets in cardiovascular disease. ADAMTSL2, ADAMTSL3 and ADAMTSL6 genetic variants have been identified in diseases of the heart and vasculature. Biallelic ADAMTSL2 variants cause the rare and deadly syndromes Geleophysic dysplasia and Al-Gazali dysplasia with several cardiac manifestations [10]. ADAMTSL3 is involved in rare chromosomal disorders with cardiovascular malformations [29, 45]. ADAMTSL6 heterozygous mutations give rise to aortic aneurysms [8]. ADAMTSLs have potential as circulatory biomarkers of cardiac fibrosis. ADAMTSL2 is a demonstrated biomarker of liver fibrosis [6] and predicts adverse events in heart failure [5], and ADAMTSL1 is independently associated with cardiac fibrosis in heart failure [4]. ADAMTSL proteins may be therapeutic targets to limit TGFβ activity in the heart and vasculature by overexpression or recombinant peptide delivery. Created with BioRender.com