Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets.

Related collections

Most cited references 111

Record: found
Abstract: found
Article: not found

Coronary calcium as a predictor of coronary events in four racial or ethnic groups.

Robert Detrano, Alan Guerci, J Carr … (2008)

In white populations, computed tomographic measurements of coronary-artery calcium predict coronary heart disease independently of traditional coronary risk factors. However, it is not known whether coronary-artery calcium predicts coronary heart disease in other racial or ethnic groups. We collected data on risk factors and performed scanning for coronary calcium in a population-based sample of 6722 men and women, of whom 38.6% were white, 27.6% were black, 21.9% were Hispanic, and 11.9% were Chinese. The study subjects had no clinical cardiovascular disease at entry and were followed for a median of 3.8 years. There were 162 coronary events, of which 89 were major events (myocardial infarction or death from coronary heart disease). In comparison with participants with no coronary calcium, the adjusted risk of a coronary event was increased by a factor of 7.73 among participants with coronary calcium scores between 101 and 300 and by a factor of 9.67 among participants with scores above 300 (P<0.001 for both comparisons). Among the four racial and ethnic groups, a doubling of the calcium score increased the risk of a major coronary event by 15 to 35% and the risk of any coronary event by 18 to 39%. The areas under the receiver-operating-characteristic curves for the prediction of both major coronary events and any coronary event were higher when the calcium score was added to the standard risk factors. The coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States. No major differences among racial and ethnic groups in the predictive value of calcium scores were detected. Copyright 2008 Massachusetts Medical Society.

0 comments Cited 640 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.

Philip Greenland, Laurie LaBree, Stanley Azen … (2004)

Guidelines advise that all adults undergo coronary heart disease (CHD) risk assessment to guide preventive treatment intensity. Although the Framingham Risk Score (FRS) is often recommended for this, it has been suggested that risk assessment may be improved by additional tests such as coronary artery calcium scoring (CACS). To determine whether CACS assessment combined with FRS in asymptomatic adults provides prognostic information superior to either method alone and whether the combined approach can more accurately guide primary preventive strategies in patients with CHD risk factors. Prospective observational population-based study, of 1461 asymptomatic adults with coronary risk factors. Participants with at least 1 coronary risk factor (>45 years) underwent computed tomography (CT) examination, were screened between 1990-1992, were contacted yearly for up to 8.5 years after CT scan, and were assessed for CHD. This analysis included 1312 participants with CACS results; excluded were 269 participants with diabetes and 14 participants with either missing data or had a coronary event before CACS was performed. Nonfatal myocardial infarction (MI) or CHD death. During a median of 7.0 years of follow-up, 84 patients experienced MI or CHD death; 70 patients died of any cause. There were 291 (28%) participants with an FRS of more than 20% and 221 (21%) with a CACS of more than 300. Compared with an FRS of less than 10%, an FRS of more than 20% predicted the risk of MI or CHD death (hazard ratio [HR], 14.3; 95% confidence interval [CI]; 2.0-104; P =.009). Compared with a CACS of zero, a CACS of more than 300 was predictive (HR, 3.9; 95% CI, 2.1-7.3; P<.001). Across categories of FRS, CACS was predictive of risk among patients with an FRS higher than 10% (P<.001) but not with an FRS less than 10%. These data support the hypothesis that high CACS can modify predicted risk obtained from FRS alone, especially among patients in the intermediate-risk category in whom clinical decision making is most uncertain.

0 comments Cited 305 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.

Vivian Barry-Hamilton, Rhyannon Spangler, Derek Marshall … (2010)

We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.

0 comments Cited 262 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Biomolecules

Journal ID (iso-abbrev): Biomolecules

Journal ID (publisher-id): biomolecules

Title: Biomolecules

Publisher: MDPI

ISSN (Electronic): 2218-273X

Publication date (Electronic): 14 October 2019

Publication date Collection: October 2019

Volume: 9

Issue: 10

Electronic Location Identifier: 610

Affiliations

[1 ]Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain; jose.martinez@ 123456iibb.csic.es (J.M.-G.);

[2 ]CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain

[3 ]Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), 08041 Barcelona, Spain

[4 ]Institut de Recerca Hospital de la Santa Creu i Sant Pau-Programa ICCC, 08025 Barcelona, Spain

[5 ]Departmento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz, 28029 Madrid, Spain

[6 ]Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid-Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain

Author notes

[* ]Correspondence: crodriguezs@ 123456santpau.cat

Author information

José Martínez-González https://orcid.org/0000-0002-3894-7166

María Galán https://orcid.org/0000-0002-4758-8388

Cristina Rodríguez https://orcid.org/0000-0002-6472-5647

Article

Publisher ID: biomolecules-09-00610

DOI: 10.3390/biom9100610

PMC ID: 6843517

PubMed ID: 31615160

SO-VID: 7cf5c155-e852-4f60-adf3-a7314efdde42

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges

Read this article at

Abstract

Related collections

Cardiovascular Innovations and Applications

Most cited references 111

Coronary calcium as a predictor of coronary events in four racial or ethnic groups.

Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.

Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 203

Cited by 26

Most referenced authors 1,402