LOX family members contribute significantly to the detrimental effects of cardiac remodelling, highlighting LOX inhibition as a potential therapeutic strategy for post-infarction recovery.

Our data show that elevated LH2b expression is associated with the persistent nature of TGF-β-induced fibrosis. Also in experimental OA, LH2b expression as well as the number of hydroxypyridinoline cross-link were significantly upregulated. We propose that LH2b, and the subsequent increase in pyridinoline cross-links, is responsible for the persistent fibrosis in experimental OA.

Patients with Marfan syndrome (MFS) are at high risk of life-threatening aortic dissections. The condition is caused by mutations in the gene encoding fibrillin-1, an essential component in the formation of elastic fibers. While experimental findings in animal models of the disease have shown the involvement of transforming growth factor-β (TGF-β)- and angiotensin II-dependent pathways, alterations in the vascular extracellular matrix (ECM) may also play a role in the onset and progression of the aortic disease. Lysyl oxidases (LOX) are extracellular enzymes, which initiates the formation of covalent cross-linking of collagens and elastin, thereby contributing to the maturation of the ECM. Here we have explored the role of LOX in the formation of aortic aneurysms in MFS. We show that aortic tissue from MFS patients and MFS mouse model (Fbn1(C1039G/+)) displayed enhanced expression of the members of the LOX family, LOX and LOX-like 1 (LOXL1), and this is associated with the formation of mature collagen fibers. Administration of a LOX inhibitor for 8weeks blocked collagen accumulation and aggravated elastic fiber impairment, and these effects correlated with the induction of a strong and rapidly progressing aortic dilatation, and with premature death in the more severe MFS mouse model, Fbn1(mgR/mgR), without any significant effect on wild type animals. This detrimental effect occurred preferentially in the ascending portion of the aorta, with little or no involvement of the aortic root, and was associated to an overactivation of both canonical and non-canonical TGF-β signaling pathways. The blockade of angiotensin II type I receptor with losartan restored TGF-β signaling activation, normalized elastic fiber impairment and prevented the aortic dilatation induced by LOX inhibition in Fbn1(C1039G/+) mice. Our data indicate that LOX enzymes and LOX-mediated collagen accumulation play a critical protective role in aneurysm formation in MFS.

Adipose tissue (AT) has a modulating role in obesity-induced metabolic complications like type 2 diabetes mellitus (T2DM) via the production of so-called adipokines such as leptin, adiponectin, and resistin. The adipokines are believed to influence other tissues and to affect insulin resistance, liver function, and to increase the risk of T2DM. In this study, we examined the impact of intervention with the short-chain fatty acid butyrate following a high-fat diet (HFD) on AT function and other metabolic risk factors associated with obesity and T2DM in mice during mid- and late life. In both mid- and late adulthood, butyrate reduced HFD-induced adipocyte hypertrophy and elevations in leptin levels, which were associated with body weight, and cholesterol and triglyceride levels. HFD feeding stimulated macrophage accumulation primarily in epididymal AT in both mid- and late life adult mice, which correlated with liver inflammation in late adulthood. In late-adult mice, butyrate diminished increased insulin levels, which were related to adipocyte size and macrophage content in epididymal AT. These results suggest that dietary butyrate supplementation is able to counteract HFD-induced detrimental changes in AT function and metabolic outcomes in late life. These changes underlie the obesity-induced elevated risk of T2DM, and therefore it is suggested that butyrate has potential to attenuate risk factors associated with obesity and T2DM.

Purpose: Exosomes containing proteins, microRNAs and mRNAs are found in extracellular spaces such as blood and other body fluids and function as messengers in cell-cell communication through transfer of their molecular content. We hypothesize that exosomes containing miRNAs function in a novel communication mechanism among joint cells in osteoarthritis (OA) pathogenesis. We previously observed that the balance of anabolic and catabolic gene expression in chondrocytes was impaired by exosomes derived from OAsynovial fibroblasts (SFB). Angiogenesis in various joint tissues, including synovium, ligaments, menisci and the osteochondral junction, is a recently recognized important factor in OA pathogenesis. The purpose of this study was to investigate potential angiogenic function of exosomes from OA-SFB. Methods: Human SFB were obtained from a normal, OA and rheumatoid arthritis (RA) knee joints, and cultured with or without interleukin-1b (IL-1b). Exosomes were isolated by ExoQuick from IL-1b stimulated medium and control medium. Isolated exosomes fraction was measured for protein content using BCA protein assay kit. To examine the angiogenic functions of exosomes derived from SFB, we examined whether migration and tube formation in human umbilical vein endothelial cells (HUVECs) were affected by normal-, OA-, RA-SFB derived exosomes. Migration assay was evaluated using HUVECs in a modified Boyden chamber. In the tube formation assay, HUVECs were seeded into plates coated with growth-factor-reduced Matrigel and tube length was measured. miRNA profiles in the exosome preparations were established using 3D-Gene miRNA microarray. Results: Migration and tube formation activity were significantly higher in endothelial cells treated with exosomes from OA and RA SFB as compared to exosomes from normal SFB. IL-1b stimulation of SFB enhanced the angiogenic activity in their exosomes. However, migration and tube formation were not induced in endothelial cells by cytokine IL-1b alone. miRNA array data showed that 349 miRNAs were changed in OA SFB exosomes as compared to normal SFB expsomes. OA-and RA-SFB exosomes shared 29 miRNAs that were up-regulated and 35 miRNAs that were down-regulated compared normal SFB exosomes. This includes several differentially expressed angiogenesis-related miRNAs. Conclusions: Exosomes from OA SFB accelerate angiogenic activity in HUVECs, and might be involved in OA development by promoting angiogenesis throughout the joint. miRNA array data suggest an OA-related miRNA profile in exosomes that may serve as a novel biomarker. These results support our hypothesis that exosomes containing miRNAs function in a novel regulatory network that contributes to various aspects of OA pathogenesis.