The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Abstract

Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1-4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter-and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders. part of the mechanoresponsive gene programs responsible for the mechanical regulation of gene expression in cardiac myocytes and fibroblasts [11]. Thus, LOX/LOXLs contribute to cardiac fibrosis, but are also active players involved in the cellular mechanisms underlying cardiac dysfunction and disease progression.In the last years, multiple studies have contributed to the understanding of the pathophysiological role of the LOX family in human diseases and, in particular, in the cardiovascular system. The involvement of this family on vascular diseases has been recently reviewed [12]. Further, LOX/LOXLs participate in a variety of processes affecting the heart, from those associated to post-myocardial infarction (MI) cardiac remodeling, cardiac hypertrophy triggered by pressure or volume overload, heart failure (HF) with preserved ejection fraction (HFPEF) associated with obesity and metabolic syndrome or atrial fibrillation. The strong impact of the alteration of LOX/LOXLs on CCL and heart function supports the interest of these family of enzymes as pharmacological targets to improve cardiac remodeling and slow the progression to HF. In this review article we focus on those findings that support the fundamental involvement of the LOX family in the mechanisms underlying cardiac damage and repair. The LOX Family of ECM-Modifying EnzymesLOX is an extracellular enzyme which governs the post-translational modification of ECM collagen and elastin. LOX catalyzes the oxidative deamination of specific ε-amino groups of lysine and hydroxylysine residues in collagen and elastin. This leads to the generation of highly reactive peptidyl α-aminoadipic γ-semialdehydes and the release of hydrogen peroxide as by-product [1-3] (Figure 1). This reactio...

Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

“…In females, the remodeling of the sarcomeric cytoskeleton in cardiomyocytes under hemodynamic load might be responsible for greater stiffness and lower LV compliance, thus resulting in more severe impairment of the cardiac function [50] than that in males. Additionally, aberrant collagen cross-linking has been reported to be more detrimental to LV diastolic and systolic performance than total collagen deposition in the ECM [4,51].…”

“…The remodeling response also encompasses adaptive changes in the extracellular matrix (ECM), including an increased deposition of fibrillar collagens, to provide a structural scaffold and signaling control to cardiac cells, thereby preserving tissue integrity and cardiac function [4]. However, these plastic changes may become maladaptive over time, thus resulting in systolic and diastolic dysfunction, heart failure and eventually death [5,6].…”

Reactive Oxygen Species and Oxidative Stress in the Pathogenesis and Progression of Genetic Diseases of the Connective Tissue

“…LOX encodes lysyl oxidases (LOXes) and it is the only TAAD-related gene acting at the ECM that has been clearly linked to oxidative stress so far. LOXes are a group of ECM enzymes that initiate the formation of covalent cross-linkages between collagen and elastin, generating H 2 O 2 as a by-product [ 188 ]. Experiments in Lox -deficient mice have shown that LOX-mediated cross-linking is essential for the maturation of the ECM, providing tensile strength [ 189 , 190 ].…”

Cells in Cardiovascular Disease: Using Diversity to Confront Adversity

“…The authors find that cultured human cardiac fibroblasts are targets of sST2, having a profibrotic effect that is prevented by NFkB inhibitors. The critical role played by cardiac fibroblasts in chronic heart disease is reflected in the number of studies of the volume that address their biological functions [ 5 , 7 , 9 , 10 , 11 ]. For instance, the study by Martin et al demonstrates that yet another mediator of inflammation, soluble phospholipase A2IIA (sPLA2-IIA), promotes myofibroblast differentiation and acts as a link between inflammation and fibrosis [ 9 ].…”

“…They dissect the role of Cx43 in a model of cardiac hypertrophy induced by angiotensin II, finding that contrasting effects could be found depending on the gene dose. This study analyzed several fibrotic markers, including lysyl oxidase (LOX), a major player in the fibrotic response to a cardiac insult and prototype of a family of extracellular matrix (ECM)-modifying enzymes essential for collagen cross-linking—an issue that is reviewed by Rodriguez et al in the present volume [ 11 ].…”