Lysyl oxidase interacts with AGE signalling to modulate collagen synthesis in polycystic ovarian tissue

Abstract

Connective tissue components – collagen types I, III and IV – surrounding the ovarian follicles undergo drastic changes during ovulation. Abnormal collagen synthesis and increased volume and density of ovarian stroma characterize the polycystic ovary syndrome (PCOS). During the ovulatory process, collagen synthesis is regulated by prolyl hydroxylase and lysyl oxidase (LOX) activity in ovarian follicles. LOX catalyzes collagen and elastin cross-linking and plays essential role in coordinating the control of ovarian extracellular matrix (ECM) during follicular development. We have recently shown accumulation of advanced glycation end products (AGEs), molecules that stimulate ECM production and abnormal collagen cross-linking, in ovarian tissue. However, the possible link between LOX and AGEs-induced signalling in collagen production and stroma formation in ovarian tissue from PCOS remains elusive. The present study investigates the hypothesis of AGE signalling pathway interaction with LOX gene activity in polycystic ovarian (PCO) tissue. We show an increased distribution and co-localization of LOX, collagen type IV and AGE molecules in the PCO tissue compared to control, as well as augmented expression of AGE signalling mediators/effectors, phospho(p)-ERK, phospho(p)-c-Jun and nuclear factor κB (NF-κB) in pathological tissue. Moreover, we demonstrate binding of AGE-induced transcription factors, NF-κB and activator protein-1 (AP-1) on LOX promoter, indicating a possible involvement of AGEs in LOX gene regulation, which may account for the documented increase in LOX mRNA and protein levels compared to control. These findings suggest that deposition of excess collagen in PCO tissue that induces cystogenesis may, in part, be due to AGE-mediated stimulation of LOX activity.

N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats

“…Recent finding from Adams et al [1] showed that Ang II increases LOX via activation of the small G protein Rac1-GTPase and the profibrotic connective tissue growth factor. Furthermore, other studies suggested that LOX gene regulation may be mediated by advanced glycation end products through binding of NFκB and activator protein-1 to the LOX promoter [23, 31]. Thus, it may be that different dependent or independent pathways of NFκB regulate cardiac LOX genes expression.…”

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction

“…Our results showed that the male Tg hearts expressed higher levels of activated LOX. Of note, both collagens and LOX are NF-B-and AP-1-responsive genes (50,51). Thus, TRAF3IP2 overexpression results in the spontaneous induction of various pro-fibrotic mediators and the development of cardiac fibrosis in the male Tg mice.…”

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

“…In addition, as mentioned previously, AGEs may induce the LOX gene and protein expression (51), thus also facilitating LOX-dependent collagen cross-linking. Under this perspective, the results of recent studies clearly demonstrated that ALT-711 or alagebrium, a breaker of AGE-related protein cross-links, ameliorated the adverse cardiac changes associated with diabetes and hypertension.…”