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

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.

Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation

“…To date, LOX has been demonstrated to regulate a diverse range of cellular processes and biological functions (Smith-Mungo and Kagan, 1998), as well as certain pathogenesis of various diseases, particularly fibrotic diseases, ischemic cardiovascular diseases, and cancer progression, which is mainly mediated by ECM remodeling and elastogenesis (Schmelzer et al, 2019), epithelialmesenchymal transition and intracellular signaling (Lopez et al, 2010;Busnadiego et al, 2013;Cox et al, 2013Cox et al, , 2015Klingberg et al, 2013;Rimar et al, 2014;Schmelzer et al, 2019). The LOX has been demonstrated as crucial contributors for normal embryonic development of various tissue and organ systems, including cardiovascular (Martinez-Gonzalez et al, 2019), and respiratory systems (Maki et al, 2002;Maki, 2009;Maki et al, 2005), as well as essential for normal physiological and cellular properties, such as sprouting angiogenesis of endothelial cells (Lucero and Kagan, 2006;Bignon et al, 2011).…”

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

“…The expression of LOX is high in the endothelium of healthy arteries and its inhibition has been linked with the endothelial dysfunction evoked by atherosclerotic risk factors, the instability and rupture of advanced atherosclerotic plaques and aortic aneurysm development [12]. Further, LOX regulates vascular smooth muscle cells (VSMC) proliferation and vascular remodeling, participates in the control of vascular stiffness, oxidative stress and calcification, and modulates platelet activation and thrombosis [12,[32][33][34]. Likewise, LOXL2 controls the age-associated increase in vascular stiffness and it is the main LOX isoenzyme contributing to neovascularization.…”

“…Likewise, LOXL2 controls the age-associated increase in vascular stiffness and it is the main LOX isoenzyme contributing to neovascularization. The mechanisms underlying the LOX/LOXLs-mediated control of vascular homeostasis have been extensively discussed [12] and are beyond the scope of this review.…”

“…Despite the potential interest of LOX inhibitors, LOX-targeting drug discovery has been hampered by the lack of LOX/LOXLs crystallographic structure, an area of active investigation, as indicate recent promising data aiming to clarify the structural-functional relationship of LOXL2 [87]. Furthermore, safety concerns should be considered, since increased expression/activity of these isoenzymes has been associated with cardiac diseases, but a decrease of LOX could underlie the development of several vascular pathologies and promote plaque instability [12]. Because cardiac and vascular pathologies frequently coexist, therapeutic approaches aiming LOX inhibition must be thoroughly evaluated to exclude undesirable side-effects.…”

“…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.…”