Role of the lysyl oxidase enzyme family in cardiac function and disease

Abstract

Heart diseases are a major cause of morbidity and mortality world-wide. Lysyl oxidase (LOX) and related LOX-like (LOXL) isoforms play a vital role in remodelling the extracellular matrix (ECM). The LOX family controls ECM formation by cross-linking collagen and elastin chains. 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. 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. 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. 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. 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. Biological approaches show potential promise but are in their infancy. 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.

Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse

“…As glomerulosclerosis remained elevated in that group, it is likely that such improvement in filtration is driven by haemodynamic mechanisms. Supporting this hypothesis, a number of studies suggested important roles of LOXs in cardiac function and vascular stiffness 41 , 42 , which could influence blood flow to the kidney. A limitation of this study is that renal haemodynamic parameters have not been measured to further elucidate this mechanism.…”

Severe congenital cutis laxa: Identification of novel homozygous LOX gene variants in two families

“…LOX (lysyl oxidase) showing location of the Tyr250 and Thr341 variants within the catalytic domain of the C‐terminal motif, which is highly conserved across species. LOX‐family catalysis is vital for elastin and collagen crosslinking in multiple tissues 18 [Colour figure can be viewed at wileyonlinelibrary.com]…”

In silico study: Potential prediction of Curcuma longa and Cymbopogon citratus essential oil as Lipoxygenase inhibitor

“…The LOX pathway that works during the process is leukotrienes and hydroperoxy fatty acids [16,17]. Nowadays, LOX has become a target for inflammatory therapy [18]. The previous study showed LOX as an anticancer [19].…”