NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.

BACKGROUND: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. METHODS: C57BL/6 mice lacking ApoE , NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal-Wallis tests were performed to determine statistical differences. RESULTS: Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3 -deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. CONCLUSION: We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.

New environmental factors related to diabetes risk in humans: Emerging bisphenols used in synthesis of plastics.

BACKGROUND: Diabetes mellitus (DM) is one of the largest global health emergencies of the 21st century. In recent years, its connection with environmental pollutants, such as bisphenol A (BPA), has been demonstrated; consequently, new structurally similar molecules are used to replace BPA in the plastics industry (BPS, BPF and BPAF). AIM: To carry out a systematic review to allow coherent evaluation of the state of the art. Subsequently, a meta-analysis was performed to unify the existing quantitative data. METHODS: Firstly, a systematic review was carried out, using the terms "(bisphenol) AND (Diabetes OR Hyperglycemia)", to maximize the number of results. Subsequently, three authors analyzed the set of articles. Finally, a meta-analysis was performed for each BP, using RevMan software. In addition, funnel plots were developed to study publication bias. RESULTS: The systematic analysis of the literature revealed 13 recent articles (2017-2023) related to the study paradigm. The qualitative analysis showed interesting data linking diabetes to the three most widely used substitute BPs in the industry: BPS, BPF and BPAF. Finally, the meta-analysis determined a positive relationship with BPS, BPF and BPAF, which was only statistically significant with BPS. CONCLUSION: There is a need to apply the precautionary principle, regulating the use of new BPs. Therefore, replacing BPA with BPS, BPF or BPAF is unlikely to protect the population from potential health risks, such as DM.