Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome.
Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome.
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饮食诱导代谢综合征小鼠模型中心肌赖氨酰氧化酶对心脏重塑的调节。
DOI：
10.1152/ajpheart.00398.2009
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Watson,RonaldR
中科院分区：
文献类型：
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作者：
Zibadi,Sherma;Vazquez,Randy;Moore,Derek;Larson,DouglasF;Watson,RonaldR
代谢综合征(METS)代表心血管疾病风险增加。尽管Met的单个成分对心脏结构和功能有不利影响，但Met的多种成分对心脏细胞外基质(ECM)的影响程度尚未得到很好的表征。赖氨酰氧化酶(LOX)是一种心脏细胞外基质修饰酶，催化形成胶原交联物。我们的目标是确定饮食诱导的蛋氨酸对LOX酶的影响。雄性C57BL/6小鼠给予高脂肪、高简单碳水化合物饲料6个月，可诱发METS。实时荧光定量聚合酶链式反应(Real-time PCR)检测基因表达。检测LOX的心肌蛋白表达和酶活性。通过组织学和羟脯氨酸测定评估肝纤维化程度。通过体内压力-容量关系的分析评估心脏的舒张功能。分析了LOX、基质金属蛋白酶及其组织抑制物，其中LOX在METS小鼠中变化最显著。尽管LOX亚型的基因表达减弱，但Mets小鼠的骨形态发生蛋白-1显著上调。相应地，与对照组相比，LOX成熟蛋白与酶原蛋白表达比增加25.9%，LOX活性增加50.0%，心肌交联型胶原增加。这种纤维化反应与舒张末压力显著增加、左心室僵硬和舒张期充盈模式受损相一致。我们的数据表明，饮食诱导的蛋氨酸改变重塑酶，主要是LOX，从而通过增加交联量改变ECM结构，导致舒张期功能障碍。
Metabolic syndrome (MetS) represents an increased risk of cardiovascular disease. Although its individual components adversely affect cardiac structure and function, the extent to which multiple components of MetS affect the cardiac extracellular matrix (ECM) has not been well characterized. Lysyl oxidase (LOX) is one of the cardiac ECM-modifying enzymes that catalyze the formation of collagen cross-linking. Our objective was to define the effect of diet-induced MetS on the LOX enzyme. MetS was induced in male C57BL/6 mice by administrating a high-fat, high-simple carbohydrate diet for 6 mo. Gene expression was determined by real-time PCR. The cardiac protein expression and enzymatic activity of LOX were measured. The severity of fibrosis was assessed by histology and hydroxylproline assay. Cardiac diastolic function was assessed by in vivo analysis of the pressure-volume relationship. LOX, matrix metalloproteinases, and their tissue inhibitors were analyzed, and of these three, LOX was most significantly changed in the MetS mice. Despite the blunted gene expression of LOX isoforms, MetS mice demonstrated a significant upregulation of bone morphogenetic protein-1. Correspondingly, there was an increase in the ratio of protein expression of mature to proenzyme LOX by 25.9%, enhanced LOX activity by 50.0%, and increased cardiac cross-linked collagen compared with the controls. This fibrotic response coincided with a marked increase in end-diastolic pressure, increased left ventricular stiffness, and impaired diastolic filling pattern. Our data signify that diet-induced MetS alters the remodeling enzymes, mainly LOX, thereby altering ECM structure by increasing the amount of cross-linking and inducing diastolic dysfunction.