Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling
Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling
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DOI：
10.1177/1535370215616511
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发表时间：
2016-03-01
影响因子：
3.2
通讯作者：
Gardner, Jason D.
中科院分区：
文献类型：
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作者：
El Hajj, Elia C.;El Hajj, Milad C.;Gardner, Jason D.
心力衰竭（HF）的一个标志是细胞外基质（ECM）的不良重塑，这是由胶原交联酶赖氨酰氧化酶（LOX）调节的。在这项研究中，我们使用HF实验模型评估LOX抑制预防不良左心室（LV）重构和功能障碍的功效。通过建立下腔静脉瘘（ACF）使Sprague-Dawley大鼠经受手术诱导的容量超负荷（VO）。LOX抑制剂β-氨基丙腈（BAPN; 100 mg/kg/天）在手术后8周给予ACF或假手术大鼠。超声心动图用于评估心室结构和功能的进行性改变。左心室（LV）导管插入术用于评估收缩力、僵硬度、LV压力和容量以及其他心功能指标的变化。通过以下方式评估LV ECM的变化：（a）胶原蛋白的组织学染色，（B）I型和III型胶原蛋白的蛋白表达，（c）羟脯氨酸测定，和（d）交联测定。LOX抑制衰减VO诱导的心脏应激增加，并衰减间质心肌胶原，总胶原，胶原蛋白I和III的蛋白水平的增加。超声心动图和导管插入术测量均表明BAPN治疗的大鼠与未治疗的大鼠相比，VO后心脏功能改善。抑制LOX可减弱VO诱导的LV僵硬度和心功能降低。总的来说，我们的数据表明，LOX抑制在容量超负荷的心脏中具有心脏保护作用。
A hallmark of heart failure (HF) is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen cross-linking enzyme, lysyl oxidase (LOX). In this study, we evaluate the efficacy of LOX inhibition to prevent adverse left ventricular (LV) remodeling and dysfunction using an experimental model of HF. Sprague-Dawley rats were subjected to surgically induced volume overload (VO) by creation of aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN; 100mg/kg/day), was administered to rats with ACF or sham surgery at eight weeks postsurgery. Echocardiography was used to assess progressive alterations in cardiac ventricular structure and function. Left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, LV pressure and volume, and other indices of cardiac function. The LV ECM alterations were assessed by: (a) histological staining of collagen, (b) protein expression of collagen types I and III, (c) hydroxyproline assay, and (d) cross-linking assay. LOX inhibition attenuated VO-induced increases in cardiac stress, and attenuated increases in interstitial myocardial collagen, total collagen, and protein levels of collagens I and III. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats vs. untreated. Inhibition of LOX attenuated VO-induced decreases in LV stiffness and cardiac function. Overall, our data indicate that LOX inhibition was cardioprotective in the volume overloaded heart.