Linking LOXL2 to Cardiac Interstitial Fibrosis

Abstract

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. CVD pathophysiology is often characterized by increased stiffening of the heart muscle due to fibrosis, thus resulting in diminished cardiac function. Fibrosis can be caused by increased oxidative stress and inflammation, which is strongly linked to lifestyle and environmental factors such as diet, smoking, hyperglycemia, and hypertension. These factors can affect gene expression through epigenetic modifications. Lysyl oxidase like 2 (LOXL2) is responsible for collagen and elastin cross-linking in the heart, and its dysregulation has been pathologically associated with increased fibrosis. Additionally, studies have shown that, LOXL2 expression can be regulated by DNA methylation and histone modification. However, there is a paucity of data on LOXL2 regulation and its role in CVD. As such, this review aims to gain insight into the mechanisms by which LOXL2 is regulated in physiological conditions, as well as determine the downstream effectors responsible for CVD development.

Keywords: DNA methylation; Lysyl Oxidase-Like 2 (LOXL2); cardiovascular disease (CVD); epigenetics; fibrosis.

Figure 1

The structure of the LOX and LOXL1–4 proteins. The C-terminal is conserved between all the LOX protein family members, containing a copper binding domain, a lysine tyrosylquinone cofactor residue and a cytokine receptor domain. At the N-terminals, LOX and LOXL1 contain pro-sequences, with LOXL1 containing a proline-rich region (PRR), while LOXL2–4 contain scavenger receptor cysteine-rich domains (SRCR) within the N-terminal. (Image adapted from Wu 2015 [50]).

Figure 2

The mechanism of lyslyl oxidase collagen cross-linking. LOX catalyzes the conversion of lysine and hydroxylysine to lysine aldehyde and hydroxylysine aldehyde, respectively. This occurs within the telopeptide region of the procollagen molecules. The propeptide fragments of these molecules are then truncated to form tropocollagen molecules, which self-assemble and form cross-links, thereby forming collagen fibrils.

Figure 3

LOXL2-induced cardiac fibrosis. Under stress conditions such as inflammation, the activation of NFκB causes increased mRNA expression of LOXL2 and downstream, LOXL2 activates the PI3K/AKT/mTOR pathway, increasing TGF-β and triggering fibroblasts differentiation, where myofibroblasts secrete α-SMA and increase collagen deposition. Overstimulation of this process results in ECM deposition and fibrosis.

Figure 4

A proposed mechanism by which LOXL2 causes fibrosis and cardiac dysfunction. LOXL2 acts via the PI3K/AKT/mTOR pathway to activate TGF-β signaling and HIF-1 protein expression. GAL3 also activates TGF-β signaling, thus with possible similar effects as LOXL2. TGF-β signaling results in an increase in α-SMA, CTGF and LOXL2 expression, which leads to an increase in collagen deposition and cross-linking, resulting in fibrosis, ventricular stiffness and cardiac dysfunction. Inflammation causes an increase in NFκB which interacts with AP1 and Sp-1 proteins, also increasing LOXL2 expression. Dysregulation of HIF-1 protein expression results in the disruption of oxygen homeostasis in the heart, also having pathological effects. Further investigation is needed to find out whether there is a direct interaction between LOXL2 and GAL3.