Involvement of lysyl oxidase in the pathogenesis of arterial stiffness in chronic kidney disease.
Involvement of lysyl oxidase in the pathogenesis of arterial stiffness in chronic kidney disease.
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赖氨酰氧化酶参与慢性肾病动脉硬化的发病机制。
DOI：
10.1152/ajprenal.00239.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mohandas,Rajesh
中科院分区：
文献类型：
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作者：
Sharma,RavindraK;Kamble,ShyamH;Krishnan,Suraj;Gomes,Joshua;To,Brandon;Li,Shiyu;Liu,I-Chia;Gumz,MichelleL;Mohandas,Rajesh
慢性肾脏病（CKD）患者发生不良心血管事件的风险增加。CKD与动脉硬化增加相关，而动脉硬化改善与更好的生存率相关。然而，CKD早期动脉僵硬度增加，这表明可能有肾脏疾病特有的其他因素增加动脉僵硬度。赖氨酰氧化酶（LOX）是胶原交联和基质重塑的关键介质。LOX主要在心血管系统中表达，其上调与组织硬化和细胞外基质重塑增加有关。因此，本研究旨在评价LOX活性增加在CKD中诱导主动脉僵硬中的作用，以及LOX抑制剂β-氨基丙腈（BAPN）是否可以通过减少胶原交联来预防主动脉僵硬。对8周龄雄性C57 BL/6小鼠进行5/6肾切除术（Nx）或假手术。手术后两周，将小鼠随机分配至BAPN（300 mg/kg/天，在水中）或载体治疗4周。使用多普勒超声通过脉搏波速度（PWV）评估主动脉僵硬度。通过ELISA评估LOX的主动脉水平，并通过质谱和Sircol测定分析交联的总胶原水平。与对照组小鼠相比，Nx小鼠显示PWV和主动脉壁重塑增加。Nx小鼠主动脉中胶原交联的增加与总胶原的增加平行。相比之下，接受BAPN治疗的Nx小鼠与接受载体治疗的相比显示出降低的交联胶原和PWV。我们的研究结果表明LOX可能是CKD患者主动脉僵硬度的早期和关键介质。新&值得注意的是CKD患者的动脉僵硬度与不良心血管结局相关。然而，CKD患者主动脉僵硬度增加的机制尚不清楚。在此，我们证明：1）CKD患者主动脉僵硬度增加与高血压和钙化无关; 2）LOX介导的细胞外基质变化至少部分导致CKD患者主动脉僵硬度增加。预防过量LOX可能在缓解CKD患者主动脉僵硬度增加和改善心血管疾病方面具有治疗潜力。
Patients with chronic kidney disease (CKD) are at increased risk for adverse cardiovascular events. CKD is associated with increases in arterial stiffness, whereas improvements in arterial stiffness correlate with better survival. However, arterial stiffness is increased early in CKD, suggesting that there might be additional factors, unique to kidney disease, that increase arterial stiffness. Lysyl oxidase (LOX) is a key mediator of collagen cross linking and matrix remodeling. LOX is predominantly expressed in the cardiovascular system, and its upregulation has been associated with increased tissue stiffening and extracellular matrix remodeling. Thus, this study was designed to evaluate the role of increased LOX activity in inducing aortic stiffness in CKD and whether β-aminopropionitrile (BAPN), a LOX inhibitor, could prevent aortic stiffness by reducing collagen cross linking. Eight-week-old male C57BL/6 mice were subjected to 5/6 nephrectomy (Nx) or sham surgery. Two weeks after surgery, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle treatment for 4 wk. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound. Aortic levels of LOX were assessed by ELISA, and cross-linked total collagen levels were analyzed by mass spectrometry and Sircol assay. Nx mice showed increased PWV and aortic wall remodeling compared with control mice. Collagen cross linking was increased in parallel with the increases in total collagen in the aorta of Nx mice. In contrast, Nx mice that received BAPN treatment showed decreased cross-linked collagens and PWV compared with that received vehicle treatment. Our results indicated that LOX might be an early and key mediator of aortic stiffness in CKD.NEW & NOTEWORTHYArterial stiffness in CKD is associated with adverse cardiovascular outcomes. However, the mechanisms underlying increased aortic stiffness in CKD are unclear. Herein, we demonstrated that1) increased aortic stiffness in CKD is independent of hypertension and calcification and2) LOX-mediated changes in extracellular matrix are at least in part responsible for increased aortic stiffness in CKD. Prevention of excess LOX may have therapeutic potential in alleviating increased aortic stiffness and improving cardiovascular disease in CKD.