Linking LOXL2 to Cardiac Interstitial Fibrosis

Erasmus, M.; Samodien, Ebrahim; Lecour, Sandrine; Cour, Martin; Lorenzo, Óscar; Dludla, Phiwayinkosi V.; Johnson, Rabia

doi:10.3390/ijms21165913

Cited by 24 publications

(28 citation statements)

References 107 publications

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“…In the present study, we found that LOXL2 and LOXL3 protein levels are enhanced, while the protein level of LOXL4 is reduced in patients with TAAD compared to normal subjects. Although LOXL2 has been widely studied in cancer and fibrotic diseases such as idiopathic pulmonary fibrosis, liver fibrosis, and cardiac fibrosis ( 34 ), its expression and function in AD were unclear. Our results showed that compared with that in non-AD aorta samples, the protein level of LOXL2 in the aortas of patients with TAAD was remarkably increased.…”

Section: Discussionmentioning

confidence: 99%

The Expression Patterns and Roles of Lysyl Oxidases in Aortic Dissection

Zhou

Chen

et al. 2021

Front. Cardiovasc. Med.

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Background: Lysyl oxidases (LOXs), including LOX, LOXL1, LOXL2, LOXL3, and LOXL4, catalyze the formation of a cross-link between elastin (ELN) and collagen. Multiple LOX mutations have been shown to be associated with the occurrence of aortic dissection (AD) in humans, and LOX-knockout mice died during the perinatal period due to aortic aneurysm and rupture. However, the expression levels and roles of other LOX members in AD remain unknown.Methods: A total of 33 aorta samples of AD and 15 normal aorta were collected for LOXs mRNA and protein levels detection. We also analyzed the datasets of AD in GEO database through bioinformatics methods. LOXL2 and LOXL3 were knocked down in primary cultured human aortic smooth muscle cells (HASMCs) via lentivirus.Results: Here, we show that the protein levels of LOXL2 and LOXL3 are upregulated, while LOXL4 is downregulated in AD subjects compared with non-AD subjects, but comparable protein levels of LOX and LOXL1 are detected. Knockdown of LOXL2 suppressed MMP2 expression, the phosphorylation of AKT (p-AKT) and S6 (p-S6), but increased the mono-, di-, tri-methylation of H3K4 (H3K4me1/2/3), H3K9me3, and p-P38 levels in HASMCs. These results indicate that LOXL2 is involved in regulation of the extracellular matrix (ECM) in HASMCs. In contrast, LOXL3 knockdown inhibited PCNA and cyclin D1, suppressing HASMC proliferation. Our results suggest that in addition to LOX, LOXL2 and LOXL3 are involved in the pathological process of AD by regulating ECM and the proliferation of HASMCs, respectively. Furthermore, we found that LOXL2 and LOXL4 was inhibited by metformin and losartan in HASMCs, which indicated that LOXL2 and LOXL4 are the potential targets that involved in the therapeutic effects of metformin and losartan on aortic or aneurysm expansion.Conclusions: Thus, differential regulation of LOXs might be a novel strategy to prevent or treat AD.

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Section: Discussionmentioning

confidence: 99%

The Expression Patterns and Roles of Lysyl Oxidases in Aortic Dissection

Zhou

Chen

et al. 2021

Front. Cardiovasc. Med.

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“…Similar to these results, previous studies also reported the overexpression of LOX and LOXL-2 in various pathological conditions characterized by fibrotic phenotypes, including IPF, renal fibrosis, cardiac fibrosis, skin aging and systemic sclerosis. Moreover, inhibition of LOX and LOXL-2 expression reduced fibrosis in animal models [ 14 , 15 , 16 , 17 , 18 ]. These findings indicated that LOX and LOX-like family members can serve as potential therapeutic targets in skin fibrosis and keloid scar tissue formation.…”

Section: Discussionmentioning

confidence: 99%

“…Collagens are synthesized by activated myofibroblasts, with their synthesis and degradation orchestrated by various enzymes, including several catabolic matrix metalloproteinases (MMPs) for degradation of collagens as well as anabolic lysyl oxidase (LOX) and four lysyl oxidase-like (LOXL) family members that covalently form cross-links between collagens [ 13 ]. Thus, emerging evidence reveals that the LOX and LOXL family are involved in various diseases related to pathogenic tissue fibrosis, including idiopathic pulmonary fibrosis (IPF), renal fibrosis, cardiac fibrosis, hepatic fibrosis and systemic sclerosis [ 14 , 15 , 16 , 17 , 18 ]. However, their potential implications in keloid skin disorders are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Ameliorating Fibrotic Phenotypes of Keloid Dermal Fibroblasts through an Epidermal Growth Factor-Mediated Extracellular Matrix Remodeling

Kim

Anggradita

Lee

et al. 2021

IJMS

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Keloid and hypertrophic scars are skin fibrosis-associated disorders that exhibit an uncontrollable proliferation of fibroblasts and their subsequent contribution to the excessive accumulation of extracellular matrix (ECM) in the dermis. In this study, to elucidate the underlying mechanisms, we investigated the pivotal roles of epidermal growth factor (EGF) in modulating fibrotic phenotypes of keloid and hypertrophic dermal fibroblasts. Our initial findings revealed the molecular signatures of keloid dermal fibroblasts and showed the highest degree of skin fibrosis markers, ECM remodeling, anabolic collagen-cross-linking enzymes, such as lysyl oxidase (LOX) and four LOX-like family enzymes, migration ability, and cell–matrix traction force, at cell–matrix interfaces. Furthermore, we observed significant EGF-mediated downregulation of anabolic collagen-cross-linking enzymes, resulting in amelioration of fibrotic phenotypes and a decrease in cell motility measured according to the cell–matrix traction force. These findings offer insight into the important roles of EGF-mediated cell–matrix interactions at the cell–matrix interface, as well as ECM remodeling. Furthermore, the results suggest their contribution to the reduction of fibrotic phenotypes in keloid dermal fibroblasts, which could lead to the development of therapeutic modalities to prevent or reduce scar tissue formation.

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“…Constitutive knockdown of fz3, Glo1, and Loxl2 improved fly lifespan. Because Loxl2 plays a role in cardiac aging in humans [71], cardiac arrhythmia and fibrotic measures were examined under Loxl2 RNAi. Age-related changes in collagen filament width and arrhythmia were improved in Loxl2 knockdown flies.…”

Section: Aging In Different Organs and Organellesmentioning

confidence: 99%