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

TY - JOUR

T1 - Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling

AU - Barallobre-Barreiro, Javier

AU - Radovits, Tamás

AU - Fava, Marika

AU - Mayr, Ursula

AU - Lin, Wen-Yu

AU - Ermolaeva, Elizaveta

AU - Martínez-López, Diego

AU - Lindberg, Eric L

AU - Duregotti, Elisa

AU - Daróczi, László

AU - Hasman, Maria

AU - Schmidt, Lukas E

AU - Singh, Bhawana

AU - Lu, Ruifang

AU - Baig, Ferheen

AU - Siedlar, Aleksandra Malgorzata

AU - Cuello, Friederike

AU - Catibog, Norman

AU - Theofilatos, Konstantinos

AU - Shah, Ajay M

AU - Crespo-Leiro, Maria G

AU - Doménech, Nieves

AU - Hübner, Norbert

AU - Merkely, Béla

AU - Mayr, Manuel

PY - 2021/12/21

Y1 - 2021/12/21

N2 - BACKGROUND: Remodeling 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 sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown.METHODS: Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5ΔCat). Proteomics was applied to study ECM remodeling in left ventricular samples from patients with HF, 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 patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5ΔCat mice, angiotensin II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin β1, filamin A, and connexin 43. Echocardiographic assessment of Adamts5ΔCat mice revealed a reduced ejection fraction and an impaired global longitudinal strain on angiotensin II infusion. Cardiac hypertrophy and collagen deposition were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from patients with ischemic HF (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, patients with HF 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 characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.

AB - BACKGROUND: Remodeling 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 sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown.METHODS: Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5ΔCat). Proteomics was applied to study ECM remodeling in left ventricular samples from patients with HF, 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 patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5ΔCat mice, angiotensin II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin β1, filamin A, and connexin 43. Echocardiographic assessment of Adamts5ΔCat mice revealed a reduced ejection fraction and an impaired global longitudinal strain on angiotensin II infusion. Cardiac hypertrophy and collagen deposition were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from patients with ischemic HF (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, patients with HF 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 characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.

KW - ADAMTS5 Protein/metabolism

KW - Animals

KW - Extracellular Matrix/metabolism

KW - Heart Failure/metabolism

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Proteoglycans/metabolism

KW - Proteomics

U2 - 10.1161/CIRCULATIONAHA.121.055732

DO - 10.1161/CIRCULATIONAHA.121.055732

M3 - SCORING: Journal article

C2 - 34806902

VL - 144

SP - 2021

EP - 2034

JO - CIRCULATION

JF - CIRCULATION

SN - 0009-7322

IS - 25

ER -