Biological effect of LOXL1 coding variants associated with pseudoexfoliation syndrome

Sharma, Shilpi; Martin, Sarah; Sykes, Matthew J.; Dave, Alpana; Hewitt, Alex W.; Burdon, Kathryn P.; Ronci, Maurizio; Voelcker, Nicolas H.; Craig, Jamie E

doi:10.1016/j.exer.2016.03.013

Cited by 27 publications

(25 citation statements)

References 44 publications

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“…Less information is available about LOXL1 and cardiac diseases. Nonsynonymous coding single-nucleotide polymorphisms (SNPs) in the LOXL1 gene are the major known genetic risk factor for pseudoexfoliation syndrome (XFS; OMIM#177650) [38], an aging-related systemic disease involving an abnormal ECM deposition, characterized by an increased risk of glaucoma, and a high susceptibility to heart disease among others [39]. In a model that spontaneously develops age-related cardiac-selective fibrosis, the plasminogen activator inhibitor-1 (PAI-1) knockout mice, genome-wide gene expression profiling identified Loxl1 among the most upregulated transcripts involved in profibrotic pathways [40].…”

Section: Lox Isoenzymes In the Cardiovascular Systemmentioning

confidence: 99%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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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...

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Section: Lox Isoenzymes In the Cardiovascular Systemmentioning

confidence: 99%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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“…Two common non-synonymous protein-coding variants in exon 1, rs1048661G>T (Arg141Leu) and rs3825942G>A (Gly153Asp), and one intronic variant (rs2165241T>C), conferring a 20-fold increased risk for PEX, were initially considered as the causal variants in this susceptibility locus. However, risk alleles were reversed between Caucasians and other ethnic populations, that is, Asian and black South African populations, and—although a biological effect on LOXL1 protein processing was suggested17—the exact functional roles of these missense variants in the pathogenesis of PEX have not yet been ascertained18. ‘Flipping' of risk alleles and lack of compelling evidence for their functionality prompted further search and led to identification of additional PEX-associated risk variants, rs16958477 and rs12914489, in the LOXL1 promoter region192021.…”

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confidence: 99%

Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1

et al. 2017

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Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression.

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“…[5][6][7] Although the effect sizes of PEX-associated LOXL1 risk variants were found to be unusually high (odds ratio > 10), they also commonly occurred (>80%) in healthy controls and showed significant reversal in certain populations on a genome-wide level, suggesting that they may have only limited biological significance for PEX pathogenesis. [8][9][10] Thus, the existing evidence to date suggests that additional PEX-associated genetic loci, environmental determinants, and gene-environment interactions remain to be identified.…”

mentioning

confidence: 99%