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）是美国男性和女性发病和死亡的主要原因。 CVD 也是美国最大的医疗经济负担。心力衰竭的一个标志是细胞外基质 (ECM) 重塑不良，该重塑受到胶原蛋白交联酶赖氨酰氧化酶 (LOX) 的调节。对于患病心脏中 LOX 的调节，或者 LOX 活性增加如何促进明显心力衰竭的进展，人们知之甚少。在这项研究中，我们评估了 LOX 抑制在防止心肌细胞脱离 ECM（一种称为失巢凋亡的现象）方面的功效。这最终导致心肌细胞凋亡，即程序性细胞死亡。在我们发表的研究结果和初步研究中，Sprague-Dawley 大鼠通过创建主动脉腔静脉瘘 (ACF) 受到手术诱导的容量超负荷 (VO) 的影响。手术后 8 周，对接受 ACF 或假手术的大鼠施用 LOX 抑制剂 β-氨基丙腈（BAPN；100 mg/kg/d）。这些大鼠已出现心室重塑和由 VO 引起的相关功能障碍。超声心动图和导管插入测量均表明，与未治疗的大鼠相比，BAPN 治疗的大鼠在 VO 后心脏功能有所改善。我们发现低抑制会减少左心室 (LV) 胶原蛋白，初步数据表明这种减少伴随着 I/III 胶原蛋白比例恢复到控制水平。此外，通过分析整合素表达的变化来评估疾病期间心脏功能下降的机制。 LOX 抑制减弱了 VO 诱导的整合素表达下降。总而言之，这些发现使我们推测，抑制 LOX 通过防止不良 ECM 重塑和减少导致心肌细胞凋亡的整合素表达来赋予心脏保护作用，从而维持收缩功能并预防心力衰竭。我们将使用综合方法通过解决以下具体目标来批判性地检验这一假设：1）将检验摄氧量应激引起的 LOX 活性增加促进心脏纤维化逐渐增加的预测，2）将检验收缩功能下降的预测是心肌细胞脱离和随后的细胞凋亡的结果，这是由于整合素表达减少和心肌细胞与 ECM 粘附减少造成的。拟议研究的结果将确定长期增加的心脏 LOX 表达和活性是否会促进不良的 ECM 改变和心肌细胞凋亡，从而加速心力衰竭的发展。此外，这些研究可能为针对心脏 LOX 的新疗法提供见解，以消除不良 ECM 变化、功能障碍和心力衰竭。