Cardioprotective Effects of Lysyl Oxidase Inhibition

赖氨酰氧化酶抑制的心脏保护作用

• 批准号: 9326474
• 负责人: Elia C El Hajj
• 金额: $ 4.33万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326474
• 关键词: Address; Adhesions; Animals; Anoikis; Apoptosis; Apoptotic; Attenuated; BCL2 gene; Biological; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Caspase; Catheterization; Cell Death; Cells; Chronic; Collagen; Conditioned Culture Media; Data; Disease; Diuretics; Echocardiography; Economic Burden; Economics; Effectiveness; Enzymes; Extracellular Matrix; Fellowship; Fibroblasts; Fistula; Functional disorder; Future; Health; Heart; Heart Diseases; Heart failure; Human; Hydrogen; Immunohistochemistry; In Vitro; Incidence; Integrins; Left; Measurement; Measures; Mediating; Medical Economics; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; National Research Service Awards; Operative Surgical Procedures; Oxidases; Patients; Peroxides; Property; Protein-Lysine 6-Oxidase; Publishing; Rattus; Regulation; Research; Role; Scientist; Shapes; Sprague-Dawley Rats; Stress; Testing; Time; Tissues; United States; Ventricular; Ventricular Remodeling; Western Blotting; Woman; beta Aminopropionitrile; cardiogenesis; clinical Diagnosis; coronary fibrosis; crosslink; experimental study; heart dimension/size; improved; improved functioning; in vivo; in vivo Model; inhibitor/antagonist; insight; mRNA Expression; men; mortality; novel; novel therapeutics; prevent; protein expression; sham surgery; therapy development; training opportunity

Cardiovascular disease (CVD) represents the leading cause of morbidity and mortality in the United States in both men and women. CVD also represents the greatest medical economic burden in the U.S. A hallmark of heart failure is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen-crosslinking enzyme, lysyl oxidase (LOX). Little is known about the regulation of LOX in the diseased heart, or how increased LOX activity promotes the progression to overt heart failure. In this study, we evaluate the efficacy of LOX inhibition to prevent cardiomyocyte detachment from the ECM, a phenomenon known as anoikis. This ultimately leads to cardiomyocyte apoptosis, programmed cell death. In our published findings and preliminary studies, Sprague-Dawley rats were subjected to surgically induced volume overload (VO) by creation of an aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN;100 mg/kg/d), was administered to rats with ACF or sham surgery at 8 weeks post-surgery. These rats had established ventricular remodeling and associated dysfunction caused by VO. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats versus untreated. We found that low inhibition reduced left ventricular (LV) collagen, and preliminary data indicate that this reduction was concomitant with a return to control levels of collagen I/III ratio. Further, the mechanisms underlying decreased cardiac function during disease were assessed by analyzing alterations in integrin expression. LOX inhibition attenuated VO-induced decreases in integrin expression. Altogether, these findings led us to hypothesize that inhibition of LOX confers cardioprotective effects by preventing the adverse ECM remodeling and decreased integrin expression that contributes to cardiomyocyte apoptosis, thereby maintaining systolic function and preventing heart failure. We will use an integrated approach to critically test this hypothesis by addressing the following specific aims: 1) will test the prediction that VO-stress induced increases in LOX activity promote progressive increases in cardiac fibrosis and 2) will test the prediction that decreased systolic function is a result of cardiomyocyte detachment, and subsequent apoptosis, resulting from decreased integrin expression and reduced myocyte adhesion to the ECM. Findings from the proposed studies will establish whether chronically increased cardiac LOX expression and activity promote adverse ECM alterations and cardiomyocyte apoptosis, thus accelerating the development of heart failure. Further, these studies may provide insight into novel therapies to target cardiac LOX for the regression of adverse ECM changes, dysfunction and heart failure.

心血管疾病（CVD）代表了美国和女性中美国发病率和死亡率的主要原因。 CVD还代表了美国最大的医疗经济负担，心力衰竭的标志是不良细胞外基质（ECM）重塑，该重塑受胶原蛋白链接酶，赖氨酸氧化酶（LOX）的调节。关于患病心脏中LOX的调节或LOX活动增加如何促进对明显的心力衰竭的发展知之甚少。在这项研究中，我们评估了LOX抑制作用的功效，以防止ECM的心肌细胞脱离，ECM是一种称为Anoikis的现象。这最终导致心肌细胞凋亡，程序性细胞死亡。在我们发表的发现和初步研究中，Sprague-Dawley大鼠通过创建主动脉瘘（ACF）对手术诱导的体积超负荷（VO）进行。 LOX抑制剂，β-氨基丙二醇（BAPN； 100 mg/kg/d），在手术后8周对大鼠进行ACF或假手术的大鼠。这些大鼠已经确定了由VO引起的心室重塑和相关功能障碍。超声心动图和导管插入术测量表明，在BAPN处理的大鼠与未治疗的大鼠中VO后VO改善了心脏功能。我们发现低抑制作用减少了左心室（LV）胶原蛋白，并且初步数据表明，这种减少与胶原蛋白I/III比的控制水平恢复了。此外，通过分析整联蛋白表达的改变来评估疾病期间心脏功能下降的机制。 LOX抑制作用减弱了Vo诱导的整联蛋白表达的降低。总的来说，这些发现使我们假设LOX抑制通过防止不良ECM重塑并降低整联蛋白表达，从而导致心肌细胞凋亡，从而维持收缩功能并防止心脏衰竭。 We will use an integrated approach to critically test this hypothesis by addressing the following specific aims: 1) will test the prediction that VO-stress induced increases in LOX activity promote progressive increases in cardiac fibrosis and 2) will test the prediction that decreased systolic function is a result of cardiomyocyte detachment, and subsequent apoptosis, resulting from decreased integrin expression and reduced myocyte adhesion to the ECM.拟议研究的发现将确定心脏LOX表达和活性是否会促进不良ECM的改变和心肌细胞凋亡，从而加速心力衰竭的发展。此外，这些研究可能会洞悉新的疗法，以靶向心脏LOX，以消除不良ECM变化，功能障碍和心力衰竭的回归。