Fibrosis in Atrial Fibrillation - Role of Reactive Species and MPO

Abstract

Atrial fibrosis with enhanced turnover and deposition of matrix proteins leads to inhomogeneous atrial electrical conduction and gives rise to electrical reentry circuits resulting in atrial fibrillation. The multifactorial pathogenesis of atrial fibrosis involves resident cardiac cells as well as infiltrating leukocytes, both generating and sequestering matrix metalloproteinases (MMPs), a key enzyme family involved in fibrosis. A growing body of evidence points toward an important role of reactive oxygen species (ROS) in the release and activation of pro-MMPs and the stimulation of pro-fibrotic cascades. Myeloperoxidase (MPO), a bactericidal enzyme released from activated polymorphonuclear neutrophils (PMN) is not only associated with a variety of cardiovascular diseases, but has also been shown to be mechanistically linked to atrial fibrosis and fibrillation. MPO catalyzes the generation of reactive species like hypochlorous acid, which affect intracellular signaling cascades in various cells and advance activation of pro-MMPs and deposition of atrial collagen resulting in atrial arrhythmias. Thus, inflammatory mechanisms effectively promote atrial structural remodeling and importantly contribute to the initiation and perpetuation of atrial fibrillation.

Keywords: atrial fibrillation; fibrosis; myeloperoxidase; reactive oxygen species.

Figure 1

Schematic overview of fibrotic remodeling triggered by reactive species. Neutrophils infiltrating the myocardial interstitium release MPO and ROS, which induce the activation of further neutrophils with sequestration of MPO, ROS, and pro-MMPs. Resident and leukocyte-derived pro-MMPs are converted by MPO and ROS to active MMPs, which degrade the ECM resulting in a release of ECM-protein fragments and embedded cytokines, growth factors, and MMPs. These molecules stimulate leukocytes to secrete further ROS and MPO as well as fibroblasts to differentiate into myofibroblasts. The latter produce cytokines, growth factors, pro-MMPs, and ECM proteins building up a fibrotic matrix. Abbreviations: EC, endothelial cell; ECM, extracellular matrix; MMP, matrix metalloproteinase; MPO, myeloperoxidase; PMN, polymorphonuclear neutrophil; ROS, reactive oxygen species.

Figure 2

Halogenation and peroxidase cycle of MPO. MPO reacts with H₂O₂ to form compound I, which oxidizes chloride to build the reactive oxidant hypochlorous acid (HOCl). Alternatively, compound I reacts with oxidizable molecules (RH) like ascorbate or tyrosine to form radical intermediates (Rbullet) via compound II.

Figure 3

Molecular targets of HOCl mediating fibrosis. MPO-derived HOCl leads to conversion of inactive pro-MMP to active MMP, inactivates TIMP-1 and PAI-1, which results in enhanced ECM-turnover. Activation of MAPKs in various cells initiates pro-fibrotic cascades. Abbreviations: ECM, extracellular matrix; HOCl, hypochlorous acid; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; PAI-1, plasmin activator-inhibitor-1; ROS, reactive oxygen species; TIMP-1, tissue-inhibitor of MMPs.

Figure 4

Effect of MPO on cardiac cells and leukocytes contributing to pro-fibrotic remodeling. MPO promotes the recruitment of leukocytes and initiates cytokine secretion from macrophages. Furthermore, MPO activates MAPKs in PMN via CD11b/CD18 integrins, which induces secretion of MMPs, superoxide, cytokines, and MPO. Potentially (dashed line), MPO activates pro-fibrotic pathways in cardiomyocytes via MAPKs. Abbreviations: MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; MPO, myeloperoxidase.