Large body of evidence supports the idea that microenvironment plays a critical role in several pathologies including atherosclerosis and cancer. The amount of hyaluronan (HA) is involved in the microenvironment alterations and the concentration of this polymer reflects the progression of the diseases promoting neoangiogenesis, cell migration, and inflammation. The HA synthesis is regulated by several factors: UDP sugar precursors availability and the phosphorylation of synthetic enzyme HAS2 as well as specific drugs reducing the UDP precursors. The HAS2 phosphorylation is done by AMP kinase, a sensor of cell energy. When the cells have low energy, AMP kinase is activated and modifies covalently the regulatory enzymes, blocking all biosynthetic processes and activating the energy producing metabolism. It was recently reported that the hexosamine biosynthetic pathway (HBP) may increase the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. We demonstrated that the increase of HA synthesis depends on the HAS2 post translational modification O-GlcNAcylation, which increases HA secretion modifying a residue different from the phosphorylation site of AMP kinase. In this report we highlighted the critical aspects of the post translational HAS2 regulation and its influence on HA synthesis. 1. Introduction Cardiovascular diseases are among the major causes of premature death in modern society, and its impact is increasing due to rising rates of obesity and diabetes [1]. Chronic inflammation of the blood vessel wall in conjunction with dysfunctional lipoprotein homeostasis is the underlying cause of atherosclerosis. Limited success of pharmacological and invasive-surgical (i.e., angioplasty and bypass grafting) treatments may be a result of the incomplete understanding of the biological mechanisms which control and contribute to the development of atherosclerosis. In this context the extracellular matrix (ECM) components may play a critical role. 2. Extracellular Matrix ECM not only gives the mechanical support to the cells, but also can interact with soluble factors (such as nutrients and signaling compounds) modulating the amount of molecules that reach the cells. Under this point of view, ECM remodeling due to physiological and pathological processes is critical to control cell response and the study of the ECM composition and that of enzymes involved in ECM remodeling (i.e., synthesis, degradation, and modification) can bring to the identification of new pivotal players controlling a particular event.
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