Integral role for lysyl oxidase‐like‐1 in conventional outflow tissue function and behavior

Abstract

Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in elastin fiber maintenance, is essential for the stability and strength of elastic vessels and tissues. Variants in the LOXL1 locus associate with a dramatic increase in risk of exfoliation syndrome (XFS), a systemic fibrillopathy, which often presents with ocular hypertension and exfoliation glaucoma (XFG). We examined the role of LOXL1 in conventional outflow function, the prime regulator of intraocular pressure (IOP). Using Loxl1 −/− , Loxl1 +/− , and Loxl1 +/+ mice, we observed an inverse relationship between LOXL1 expression and IOP, which worsened with age. Elevated IOP in Loxl1 −/− mice was associated with a larger globe, decreased ocular compliance, increased outflow facility, extracellular matrix (ECM) abnormalities, and dilated intrascleral veins, yet, no dilation of arteries or capillaries. Interestingly, in living Loxl1 −/− mouse eyes, Schlemm's canal (SC) was less susceptible to collapse when challenged with acute elevations in IOP, suggesting elevated episcleral venous pressure (EVP). Thus, LOXL1 expression is required for normal IOP control, while ablation results in altered ECM repair/homeostasis and conventional outflow physiology. Dilation of SC and distal veins, but not arteries, is consistent with key structural and functional roles for elastin in low-pressure vessels subjected to cyclical mechanical stress.

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

“…For example, LOX knockout mice died perinatal due to aortic aneurysms, cardiovascular dysfunction and diaphragmatic ruptures (26,27); LOXL1 de ciency induces a strong phenotype in mice with disturbance of elastic ber (28)(29)(30); general LOX inhibitor usually decreases the amount of several collagen and elastin cross-links, however it is not always able to restore tissue architecture as shown in a hyperoxia-based mouse model of bronchopulmonary dysplasia associated with aberrant late lung development (31). Recently, using Loxl1 knockout mice, Li et al found that living Loxl1 knockout mouse eyes, ocular compliance in Loxl1 knockout mice was lower than wild-type littermates (32). This was suggested that improper crosslinking of elastin and collagen was compensated by other mechanisms, for example, increased collagen content, or compensated increased the expression of other cross-linking enzymes to maintaining tissue structure.…”

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

“…Importantly, several studies of these SNPs have demonstrated that they do not appear to be associated with the pathogenesis of POAG—a key distinction since XFS/XFG is a cause of secondary open-angle glaucoma [ 174 , 175 , 176 ]. Furthermore, it has been suggested that disease is the result of build-up of LOXL1 protein in the setting of decreased cellular proteostasis capability due to aging [ 177 ], and LOXL1 has also been implicated in IOP changes, as decreased expression results in changes to ocular outflow physiology [ 178 ].…”

KLF4, a Key Regulator of a Transitive Triplet, Acts on the TGF-β Signaling Pathway and Contributes to High-Altitude Adaptation of Tibetan Pigs

“…A majority of the identified hub genes participated in the angiogenesis process, such as LOXL1, KLF4, and EGR1. The LOXL1 gene is essential for the stability and strength of elastic vessels and tissues (Li et al, 2020) and may play FIGURE 7 | The "KLF4-EGR1-BCL6B" complex and their regulated genes in Tibetan pig lung tissues. The complex formed by KLF4-EGR1-BCL6B regulates the EPAS1, SMAD6, SMAD7, KDR, ATOH8, and CCN1 genes and mediates the TGF-β and PI3K-Akt signaling pathways by regulating SMAD6, SMAD7, and KDR genes, respectively.…”