2023/11/29 by Davi da Silva Barbirato
#Biochemical Phenomena #Biological Phenomena #Cell Phenomena #Medical Sciences #Medicine and Health Sciences #Metabolism #and Immunity #and Nutrition
paper · doi:10.17605/osf.io/vzwhr
New estimates published in The Lancet indicate that more than 1.31 billion people could live with diabetes mellitus (DM) by 2050 worldwide. This disease causes life-altering morbidity, high mortality rates, and interacts with and worsens many other diseases. The increase in prevalence is driven by the increase in type 2 DM, which in turn is driven by the increase in obesity prevalence and demographic changes (The Lancet, 2023). It is a chronic, non-communicable inflammatory condition––considered a pandemic of unprecedented magnitude––characterized by elevated blood glucose levels (hyperglycemia) due to insufficient production and/or action of endogenous insulin (Sun et al., 2021). Insulin is an essential hormone secreted by the β cells of the pancreas, causing the cells to absorb glucose from the bloodstream. A relative or absolute insulin deficiency resulting from β-cell dysfunction and insulin resistance (IR) causes hyperglycemia. Furthermore, some evidence suggests that individuals with DM are at increased risk of physical and cognitive disability, cancer, tuberculosis, and depression (Zhang et al., 2020). The mechanisms linking inflammation to the development of diabetes and diabetic complications are poorly understood. Although inflammatory cytokines such as TNF (tumor necrosis factor) have induced insulin resistance by stimulating serine phosphorylation of IRS-1 (insulin receptor substrate 1) (Hotamisligil et al., 1996; Shoelson et al., 2006), the processes by which DM induces and maintains inflammation remains unclear. Hyperglycemia is important for inflammation. In in vitro experiments, high glucose levels stimulated inflammatory signaling that activates NF-B (nuclear factor B) (Yerneni et al., 1999; Chen et al., 2003; Ramana et al., 2003). In humans, an increase in plasma glucose has been associated with an acute increase in circulating cytokine levels, even in healthy individuals (Esposito et al., 2002). Vascular smooth muscle cells exposed to high levels of glucose secrete TNF that activates its receptor, stimulating NF-B-mediated gene transcription (Ramana et al., 2007). This appears to be prevented by soluble TNF receptors, suggesting the presence of an autocrine/paracrine loop linking TNF release to subsequent NF-B activation. However, the mechanisms by which hyperglycemia stimulates TNF release remain unknown. TNF is produced as a membrane-bound precursor that is processed by ADAM17 (Black et al., 1997; Moss et al., 1997). Some studies demonstrate that ADAM17 inhibition prevents inflammatory conditions, including those associated with hyperglycemia (Patel et al., 1998; Doggrell, 2002; Federici et al., 2005). However, it is still unclear whether ADAM17 is expressed in vascular tissues and whether its activation is an essential step in the processing of TNF in these tissues, exposed to high levels of glucose. According to Reddy et al. (2009), high glucose levels stimulate TNF ectodomain release in aortic smooth muscle cells, phosphorylation and activation of ADAM17. Hyperglycemia-induced ADAM17 phosphorylation and TNF processing were also prevented by TNF-protease-1 inhibitor (ADAM17 inhibitor). Furthermore, inhibition of PKC (protein kinase C) prevented hyperglycemia-induced ADAM17 activation and accumulation of unprocessed TNF. Sorbinil treatment decreased circulating levels of TNF in rats with streptozotocin-induced DM. Sorbinil also decreased the expression of TNF, MMP-2 and MMP-9, and increased TIMP3 in vascular smooth muscle cells treated with high levels of glucose and in damaged carotid arteries of rats with DM. Therefore, hyperglycemia-induced TNF release follows the activation of ADAM17, which is regulated, in part, by PKC and aldose redutase (AR). The inhibition of ADAM17 by the TNF-protease-1 inhibitor or the pharmacological inhibition of PKC or AR may represent useful strategies for the treatment of vascular inflammation associated with DM. Several potential mechanisms causing abnormal endothelial insulin signaling in type 2 DM need further investigation. ADAM17 activity and the presence of the insulin receptor appear to increase in the plasma of individuals with type 2 DM. Ghiarone et al. (2022) reported an increased expression of ADAM17, reduced TIMP3, insulin receptor alpha subunit (IR) and insulin-induced vasodilation among individuals with type 2 DM, compared to healthy individuals. Active ADAM17 was able to cleave, in vitro, the ectodomain of the subunit (IRβ). Endothelial cells overexpressing ADAM17 or exposed to PMA (protein kinase C activator) showed increased ADAM17 activity, decreased presence of IRα on the cell surface and increased insulin receptor release. Furthermore, pharmacological inhibition of ADAM17 with TAPI-0 (ADAM17 [TACE] and MMP inhibitor) rescued PMA-induced IR release and deficiencies in insulin signaling in endothelial cells, as well as insulin-stimulated vasodilation in human arteries. Therefore, the authors suggest that ADAM17-mediated IR release from the endothelial surface impairs insulin-mediated vasodilation, and inhibition of ADAM17 activity should be considered as a strategy to restore vascular insulin sensitivity in type 2 DM. Diabetes increases neointima formation after vascular procedures, manifested by accelerated proliferation and migration of vascular smooth muscle cells. Sema3G (semaphorin 3G), secreted mainly by endothelial cells, regulates diverse cellular functions and vascular pathologies. The serum level of Sema3G is increased in patients and mice with DM. Compared with control mice (controlled diet), mice fed a high-fat diet showed thicker neointima and higher Sema3G expression in the vasculature after femoral injury. Sema3G derived from endothelial cells in DM condition promoted progression and proliferation of the cell cycle of human aortic smooth muscle cells through the activation of YAP (Yes-associated protein), via Nrp2/PlexinA1, with increased expression of MMP-2 and MMP-9. These results suggest that Sema3G inhibition may represent a therapeutic alternative against intimal hyperplasia associated with DM (Luo et al., 2023). Evidence on the function and potential mechanism of endothelial cell-derived Sema3G in vascular smooth muscle cells, especially in DM conditions, remains unclear. In patients with DM, constant hyperglycemia generates oxidative stress (OS). The synthesis of MMP-9 is induced by sustained hyperglycemia. This was demonstrated at the protein level, as the expression and activity of MMP-9 increased as a consequence of the OS generated in vascular endothelial cells (Uemura et al., 2001). TIMP-1 can mitigate the death of β cells in type 1 DM, because it enhances the replication of pancreatic islet β cells (Jiang et al., 2007). However, TIMP-1 has also been associated with low-grade chronic inflammation in the adipose tissue of patients with T2DM (Zhang et al., 2018). Individuals with T2DM in combination with arterial hypertension exhibit maximum TIMP-1 levels and TIMP-1:MMP-2 and TIMP-1:MMP-9 ratios, as well as enhanced secretion of TNF-α, IL-6 (interleukin-6), and IL-17 (Kologrivova et al., 2014). TIMP-3 has also been implicated in the pathogenesis of DM and vascular inflammation (Fiorentino et al., 2013). TIMP-3 inhibit shedding enzymes, such as ADAM17, which are involved in inflammatory processes. In atherosclerotic plaques from subjects with T2DM, the deregulation of ADAM17 and MMP-9 activities is related to the inadequate expression of TIMP-3 via SirT1 (Cardellini et al., 2009). There is increasing evidence of the roles of MMP-2, MMP-9, MMP-11, MMP-13, and TIMP-4 in DM and metabolic disorders (Cabral-Pacheco et al., 2020). In the DM population, the expression of MMP-2 and MMP-9 is altered, which contributes to microangiopathic and macroangiopathic complications, such as nephropathy, with MMP-2 being a good index of microangiopathy severity and MMP-9 being a good marker of macroangiopathy. In ex vivo models, at the protein level, MMP-9 has shown activity in endothelial cells and regulation by high concentrations of glucose (Derosa et al., 2005). Macrophages infiltrating the glomeruli secrete MMPs, leading to an imbalance between ECM (extracellular matrix) degradation and renewal, which results in proteinuria and renal failure (Lassila et al., 2005). Animal models of diabetes have shown an inhibition of MMP proteolytic activity in renal tissues (Inada et al., 2005). The accumulation of ECM characteristic of diabetic nephropathy is partially caused by the profibrotic proteins TGF-β (transforming growth factor beta) and connective tissue growth factor. ADAM17 and its inhibitor, TIMP-3, are involved in nephropathy, and the loss of TIMP-3 underlies the development of diabetic nephropathy via FoxO1/STAT1 interplay (Fiorentino et al., 2013). It was originally thought that MMPs antagonized the development of fibrotic diseases. It has also been reported that MMP-9 plays a role in atherosclerosis development, and both MMP-2 and MMP-9, along with growth factors and cytokines, play roles in the development of proteinuria, tubulointerstitial fibrosis, and kidney disease progression (Dimas et al., 2013). MMP-2 has been related to the pathogenesis of chronic kidney disease, and its increased expression generates kidney damage as a result of ischemia–reperfusion injury. MMP-2 leads to structural alterations at the level of the tubular basement membrane and can generate all of the common features of kidney disease, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis (Cheng et al., 2006). In terms of epigenetic regulation, it has been shown that hypomethylation of the TIMP-2 gene can be associated with albuminuria in patients with early diabetic nephropathy (Aldemir et al., 2017). MicroRNAs play important roles in the initiation and progression of many pathologic processes. miR-21 contributes to renal fibrosis mediated by MMP-9/TIMP-1 and improves the glomerular lesions induced by TGF-β and hyperglycemia through the repression of proapoptotic signals, which inhibits the loss of podocytes (Wang et al., 2013). It has been proposed that miR-21 also regulates TIMP-3. According to the above discussion, the inhibition of miR-21 may be a new target for diabetic nephropathy (Cabral-Pacheco et al., 2020). In addition, increasing studies suggest that OS plays a pivotal role in the pathogenesis and progression of diabetes. Nevertheless, the precise underlying mechanisms are not yet fully understood. Type 2 DM is associated with increased OS resulting from several abnormalities, including hyperglycemia, inflammation and dyslipidemia (Paoletti et al., 2006; Bukhari et al., 2015). In turn, elevated reactive oxide species (ROS) can act as a second messenger and regulate the biological function of various proteins including IKKβ (IκB kinase β), PKC and Keap1 (Kelch-like ECH-associated protein 1) through interaction with cysteine residues (termed “redox sensors”) of these proteins (Evans et al., 2002; David et al., 2017). This dynamic modification of intracellular redox sensors by ROS is defined as redox modification, similar to protein phosphorylation, acetylation, or ubiquitination, which plays an important role in the development of diabetes (Okatan et al., 2013). Redox modification of these proteins can activate alternative downstream signaling pathways which play critical roles in impaired insulin secretion and IR, facilitating the development of DM and diabetic complications. Diabetes is characterized by hyperglycemia which leads to the overproduction of free radicals (ROS/RNS) and further increases OS due to the imbalance between ROS/RNS and antioxidants. In turn, multiple studies have suggested that OS plays a major role in the progression of DM involved with pancreatic β-cell dysfunction, IR, and diabetic complications. Although antidiabetic attempts with antioxidants, such as vitamin C/E supplementation and SOD-like mimics, these therapeutic approaches have been unsatisfactory possibly due to poor solubility, permeability, and stability. Precise therapeutic intervention is essential to inhibit ROS generation from mitochondria or non-mitochondrial sources. Recent studies suggest that the redox modification of some critical proteins (such as IKKβ, PKC and Keap1, mentioned previously) are implicated in the pathogenesis and progression of DM and diabetic end-organ damage. Therapeutic strategies targeting post-translational modification of these proteins have shown a perspective potential in the treatment of DM (Zhang et al., 2020). The therapeutic strategy of targeting MMPs/ADAMs and OS has been shown to have great potential for the treatment of DM and diabetic complications. However, it is necessary to develop novel antioxidant delivery approaches and precise drug targeting of ROS sources and redox modifications to prevent and retard the pathogenesis and progression of DM and diabetic complications. It is important to highlight the intersections between MMPs and OS, as both participate in the pathogenesis of DM. In this context, the mechanistic insight of changes in MMPs and OS in DM remains unclear. Therefore, this systematic review aims to synthesize and analyze current preclinical evidence on the intersections between MMPs and OS in the pathogenesis of DM. Here we summarize current pre-clinical evidence on the mutual interaction between MMPs and oxidative stress contributing to the pathogenesis of diabetes.