Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling

Abstract

Background: Remodelling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulphate proteoglycans (CSPGs) such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown. Methods: Versican remodelling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5 △Cat ). Proteomics was applied to study ECM remodelling in left ventricular samples from HF patients, with a particular focus on the effects of common medications used for the treatment of HF. Results: Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in ischemic HF patients. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II (Ang II) infusion. In Adamts5 △Cat mice, Ang II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin beta 1, filamin A and connexin 43. Echocardiographic assessment of Adamts5 △Cat mice revealed a reduced ejection fraction and an impaired global longitudinal strain upon Ang II infusion. Cardiac hypertrophy and collagen deposition, however, were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from ischemic HF patients (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, HF patients treated with β-blockers had a distinct cardiac ECM profile. Conclusions: Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart, and that versican accumulation is associated with impaired cardiac function. A comprehensive characterisation of the cardiac ECM in ischemic HF patients revealed that β−blockers may have a previously unrecognized beneficial effect on the cardiac CSPG content.

Comprehensive Mapping and Dynamics of Site-Specific Prolyl-Hydroxylation, Lysyl-Hydroxylation and Lysyl O-Glycosylation of Collagens Deposited in ECM During Zebrafish Heart Regeneration

“…A total of twenty-four 3-hydroxyproline sites (see Table 1 ) at the “Xaa” position of the G-Xaa-HyP motif in COL1A1a were identified. Out of these, 10 sites (P 176 , P 551 , P 755 , P 800 , P 869 , P 881 , P 911 , P 1103 , P 1106 , and P 1148 ) are evolutionarily conserved in mice ( Padmanabhan Iyer et al, 2016 ) and human heart tissue ( Barallobre-Barreiro et al, 2021 ) ( Figure 4 ; Table 1 , Supplementary Figure S2 and Supplementary Figure S3 ). This highlights probable conserved functions of these sites in collagen molecule providing structural support and maintaining homeostatic ECM assembly.…”

“…Furthermore, healthy human heart sample (ECM) mass-spectrometry data from Barallobre-Barreiro et al . (PXD028908) ( Barallobre-Barreiro et al, 2021 ), and mice heart sample (ECM) mass-spectrometry data from Padmanabhan et al (PXD002488) ( Padmanabhan Iyer et al, 2016 ) was reanalyzed for the site-specific collagen PTM identification.…”

Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes

“…As far as we know, VCAN, also termed as versican, is the rst time to be identi ed as a hub gene of BMLs. Versican is an extracellular matrix (ECM) component (33) secreted by stromal cells, which involves in cell adhesion, proliferation, migration, and extracellular matrix assembly (34). The aberration of versican plays critical roles in broproliferative diseases, such as exacerbating degradation of myocardial cells (Heart failure) (33), increasing activation of hepatic stellate cells (Hepatic brosis) (35) and thickening tunica intima (Ischemic cerebral small-vessel disease)(36).…”

RNA modification by M6A methylation in cardiovascular diseases: Current trends and future directions

“…By combining 16S rRNA sequencing and metabolomics analysis, Yan et al found that a high-salt diet reduces Bacteroides by changing the composition and metabolism of intestinal microflora and increasing the level of corticosterone to promote hypertension [120] . Barallobre-Barreiro et al integrated single-cell sequencing and proteomics analysis on the left ventricular tissues from HF patients and the control subjects to reveal ECM component of scar myocardium [121] .…”

“…They found the accumulations of polysaccharides and other proteoglycans in scar myocardium in patients with ischemic HF [121] . Yokota et al analyzed cardiac scar tissue of mice at 3, 7, 14, 21, and 42 days after ischemic heart injury respectively using multiple omics (transcriptomics, proteomics, and singlecell omics), screened out a key collagen gene col5a1 in scar tissue of early MI, and revealed the mechanical properties of its influence on scar tissue fibroblasts and mechanisms [122] .…”