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

Javier Barallobre-Barreiro; Tamás Radovits; Marika Fava; Ursula Mayr; Wen Yu Lin; Elizaveta Ermolaeva; Diego Martínez-López; Eric L. Lindberg; Elisa Duregotti; László Daróczi; Maria Hasman; Lukas E. Schmidt; Bhawana Singh; Ruifang Lu; Ferheen Baig; Aleksandra Malgorzata Siedlar; Friederike Cuello; Norman Catibog; Konstantinos Theofilatos; Ajay M. Shah; Maria G. Crespo-Leiro; Nieves Doménech; Norbert Hübner; Béla Merkely; Manuel Mayr

doi:10.1161/CIRCULATIONAHA.121.055732

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

Javier Barallobre-Barreiro, Tamás Radovits, Marika Fava, Ursula Mayr, Wen Yu Lin, Elizaveta Ermolaeva, Diego Martínez-López, Eric L. Lindberg, Elisa Duregotti, László Daróczi, Maria Hasman, Lukas E. Schmidt, Bhawana Singh, Ruifang Lu, Ferheen Baig, Aleksandra Malgorzata Siedlar, Friederike Cuello, Norman Catibog, Konstantinos Theofilatos, Ajay M. ShahMaria G. Crespo-Leiro, Nieves Doménech, Norbert Hübner, Béla Merkely, Manuel Mayr

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

160 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	2021-2034
Number of pages	14
Journal	Circulation
Volume	144
Issue number	25
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.121.055732
Publication status	Published - 21 Dec 2021

Keywords

adrenergic beta-agonists
extracellular matrix
heart failure
proteoglycans

Access to Document

10.1161/CIRCULATIONAHA.121.055732

055732R1_Merged_PDFAccepted author manuscript, 24.5 MB
Barallobre-Barreiro_Cirulcation_AHA_2021Final published version, 28.1 MBLicence: CC BY

Cite this

Barallobre-Barreiro, J., Radovits, T., Fava, M., Mayr, U., Lin, W. Y., Ermolaeva, E., Martínez-López, D., Lindberg, E. L., Duregotti, E., Daróczi, L., Hasman, M., Schmidt, L. E., Singh, B., Lu, R., Baig, F., Siedlar, A. M., Cuello, F., Catibog, N., Theofilatos, K., ... Mayr, M. (2021). Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling. Circulation, 144(25), 2021-2034. https://doi.org/10.1161/CIRCULATIONAHA.121.055732

@article{c788bf6fa1594d9db2422110fef67d13,

title = "Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling",

abstract = "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.",

keywords = "adrenergic beta-agonists, extracellular matrix, heart failure, proteoglycans",

author = "Javier Barallobre-Barreiro and Tam{\'a}s Radovits and Marika Fava and Ursula Mayr and Lin, {Wen Yu} and Elizaveta Ermolaeva and Diego Mart{\'i}nez-L{\'o}pez and Lindberg, {Eric L.} and Elisa Duregotti and L{\'a}szl{\'o} Dar{\'o}czi and Maria Hasman and Schmidt, {Lukas E.} and Bhawana Singh and Ruifang Lu and Ferheen Baig and Siedlar, {Aleksandra Malgorzata} and Friederike Cuello and Norman Catibog and Konstantinos Theofilatos and Shah, {Ajay M.} and Crespo-Leiro, {Maria G.} and Nieves Dom{\'e}nech and Norbert H{\"u}bner and B{\'e}la Merkely and Manuel Mayr",

year = "2021",

month = dec,

day = "21",

doi = "10.1161/CIRCULATIONAHA.121.055732",

language = "English",

volume = "144",

pages = "2021--2034",

journal = "Circulation",

issn = "1524-4539",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "25",

}

Barallobre-Barreiro, J, Radovits, T, Fava, M , Mayr, U, Lin, WY, Ermolaeva, E, Martínez-López, D, Lindberg, EL, Duregotti, E, Daróczi, L, Hasman, M , Schmidt, LE , Singh, B , Lu, R , Baig, F, Siedlar, AM, Cuello, F , Catibog, N , Theofilatos, K , Shah, AM, Crespo-Leiro, MG, Doménech, N, Hübner, N, Merkely, B & Mayr, M 2021, 'Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling', Circulation, vol. 144, no. 25, pp. 2021-2034. https://doi.org/10.1161/CIRCULATIONAHA.121.055732

TY - JOUR

T1 - Extracellular Matrix in Heart Failure

T2 - 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 - adrenergic beta-agonists

KW - extracellular matrix

KW - heart failure

KW - proteoglycans

UR - http://www.scopus.com/inward/record.url?scp=85122903981&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.121.055732

DO - 10.1161/CIRCULATIONAHA.121.055732

M3 - Article

C2 - 34806902

AN - SCOPUS:85122903981

SN - 1524-4539

VL - 144

SP - 2021

EP - 2034

JO - Circulation

JF - Circulation

IS - 25

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this