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Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling
Circulation ( IF 37.8 ) Pub Date : 2021-11-22 , DOI: 10.1161/circulationaha.121.055732
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

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.

中文翻译:

心力衰竭中的细胞外基质:ADAMTS5 在蛋白多糖重塑中的作用

背景:细胞外基质 (ECM) 的重塑是心力衰竭 (HF) 的标志。我们之前对小鼠心脏成纤维细胞分泌组的分析返回 ADAMTS5(一种具有血小板反应蛋白基序的去整合素和金属蛋白酶 5)作为最丰富的蛋白酶之一。ADAMTS5 切割硫酸软骨素蛋白聚糖,例如多功能蛋白聚糖。ADAMTS5 及其底物 versican 对 HF 的贡献尚不清楚。方法:在缺乏 ADAMTS5 催化结构域的小鼠中评估 Versican 重塑(Adamts5 ΔCat)。蛋白质组学用于研究 HF 患者左心室样本中的 ECM 重塑,特别关注用于治疗 HF 的常用药物的效果。结果:Versican 和 versikine(一种 ADAMTS 特异性 versican 切割产品)在患者体内积累与缺血性 HF。Versikine 在心脏缺血/再灌注损伤的猪模型和血管紧张素 II 输注后的小鼠心脏中也升高。在 Adamts5 ΔCat小鼠中,血管紧张素 II 输注导致 versican 积聚和透明质酸紊乱,同时整合素 β1、细丝蛋白 A 和连接蛋白 43 水平降低。 Adamts5 ΔCat的超声心动图评估小鼠在血管紧张素 II 输注时显示射血分数降低和整体纵向应变受损。心脏肥大和胶原沉积与同窝对照相似。在对来自缺血性 HF 患者(n = 65)的大量心脏外植体进行蛋白质组学分析时,使用 β 受体阻滞剂与 ECM 沉积减少有关,其中 versican 是最显着的变化之一。随后的心脏成纤维细胞实验证实,β1-肾上腺素能受体刺激增加了多功能蛋白聚糖的表达。尽管有相似的临床特征,但接受 β 受体阻滞剂治疗的 HF 患者具有明显的心脏 ECM 特征。结论:我们在动物模型和患者中的结果表明,ADAMTS 蛋白酶对心脏中的多功能蛋白聚糖降解至关重要,并且多功能蛋白聚糖的积累与心脏功能受损有关。对缺血性 HF 患者心脏 ECM 的综合表征表明,β-受体阻滞剂可能对心脏硫酸软骨素蛋白多糖含量具有以前未被认识的有益作用。
更新日期:2021-12-20
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