12 AF is the most common sustained arrhythmia and is associated with adverse outcomes such as stroke, HF, and death. 11 Cardiac fibrosis also impedes propagation of the cardiac impulse, leading to arrhythmias such as atrial fibrillation (AF). 10 HF is associated with substantial morbidity and mortality. 1, 8įibrosis impairs myocardial relaxation and causes diastolic dysfunction, 9 increasing the probability of HF development. 4–6 Under normal conditions, there is a balance between synthesis and degradation of fibrillar collagen 7 when the heart is injured, or exposed to a range of pathological stressors, collagen accumulation exceeds degradation, producing fibrosis. 3 While fibrosis is crucial for wound healing as occurs in MI, 4 maladaptive fibrosis leads to stiffening of the ventricles and progression of heart failure (HF). 1, 2 Fibrosis is a complex process, characterized by excessive secretion by fibroblasts of ECM-related proteins, including procollagen and fibronectin, insoluble collagen and enzymes that modify structural ECM proteins. Fibrotic expansion of the ECM is a characteristic part of the cardiac response to many stressors and pathologies, including pressure overload, myocardial infarction (MI), and cardiomyopathy. It establishes a skeleton into which the cellular components of the heart, notably cardiomyocytes and the vascular elements that form blood vessels, are structurally integrated to ensure proper function.
The extracellular matrix (ECM) plays a key role in cardiac function. LOX, LOX-like (LOXL) proteins, Myocardial infarction, Heart failure, Hypertrophy, Dilated cardiomyopathy, Atrial fibrillation, Fibrosis, Hypertension 1. While there is strong evidence for LOX-family protein participation in heart failure, myocardial infarction, cardiac hypertrophy, dilated cardiomyopathy, atrial fibrillation and hypertension, as well as potential interest as therapeutic targets, the precise involvement of LOX-family proteins in heart disease requires further investigation. Biological approaches show potential promise but are in their infancy. Therapeutic targeting of LOX family enzymes has shown promising results in animal models, but small-molecule approaches have been limited by non-specificity and off-target effects. The purposes of this review article are: (i) to summarize the basic biochemistry and enzyme function of LOX and LOXL proteins (ii) to consider their tissue and species distribution and (iii) to review the results of experimental studies of the roles of LOX and LOXL proteins in heart disease, addressing involvement in the mechanisms, pathophysiology and therapeutic responses based on observations in patient samples and relevant animal models. An awareness of the potential pathophysiological importance of LOX has led to the evaluation of interventions that target LOX/LOXL proteins for heart-disease therapy. Dynamic changes in LOX and LOXL protein-expression occur in a variety of cardiac pathologies these changes are believed to be central to the associated tissue-fibrosis. LOX/LOXL proteins are copper-dependent amine oxidases that catalyse the oxidation of lysine, causing cross-linking between the lysine moieties of lysine-rich proteins. The LOX family controls ECM formation by cross-linking collagen and elastin chains. Lysyl oxidase (LOX) and related LOX-like (LOXL) isoforms play a vital role in remodelling the extracellular matrix (ECM). Heart diseases are a major cause of morbidity and mortality world-wide.
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