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Objective To elucidate the mechanism whereby advanced glycation end products (AGEs) accelerate atherosclerosis (AS) and to explore novel therapeutic strategies for atherosclerotic cardiovascular disease. Methods and results The effect of AGEs on low-density lipoprotein (LDL) transcytosis across endothelial cells (ECs) was assessed using an in vitro model of LDL transcytosis. We observed that AGEs activated the receptor for advanced glycation end products (RAGE) on the surface of ECs and consequently upregulated Caveolin-1, which in turn increased caveolae-mediated LDL transcytosis and accelerated AS progression. Our molecular assessment revealed that AGEs activate the RAGE-NF-κB signaling, which then recruits the NF-κB subunit p65 to the RAGE promoter and consequently enhances RAGE transcription, thereby forming a positive feedback loop between the NF-κB signaling and RAGE expression. Increased NF-κB signaling ultimately upregulated Caveolin-1, promoting LDL transcytosis, and inhibition of RAGE suppressed AGE-induced LDL transcytosis. In ApoE −/− mice on a high-fat diet, atherosclerotic plaque formation was accelerated by AGEs but suppressed by EC-specific knockdown of RAGE. Conclusion AGEs accelerate the development of diabetes-related AS by increasing the LDL transcytosis in ECs through the activation of the RAGE/NF-κB/Caveolin-1 axis, which may be targeted to prevent or treat diabetic macrovascular complications.

Background Heqi San has shown therapeutic potential in the treatment of diabetes. This study aimed to explore the mechanism underlying the effects of Heqi San in treating rats with diabetic atherosclerosis (AS). Methods We established a model of atherosclerosis in diabetic rats and treated them with Heqi San. Body weight, food intake, and water intake were measured every two weeks. Subsequently, we examined the effects of Heqi San on serum biochemical markers, aortic structure, fat accumulation, and serum levels of inflammatory factors. The levels of p-AMPK and AMPK in thoracic aorta tissue were evaluated by western blotting. Mass spectrometry was used to identify differential serum metabolites after Heqi San treatment. Results Intragastric administration of Heqi San enhanced food intake and reduced the excessive water intake caused by diabetic atherosclerosis. Both low and high doses of Heqi San decreased elevated levels of TG, TC, LDL, GLU, and insulin, while increasing HDL levels. Additionally, the AS group showed increased expression of CD68 and CCL-2 in thoracic aorta tissue, along with elevated serum levels of IL-6, IL-1β, and TNF-α. Treatment with Heqi San reduced these inflammatory markers. Heqi San also increased p-AMPK expression in thoracic aorta tissue. Mass spectrometry analysis revealed that the AS group had significantly elevated serum levels of L-NIL, Gln_Cys_Asp, and Geshoidin, whereas high-dose Heqi San treatment decreased the levels of these metabolites. Conclusions Heqi San could alleviate atherosclerosis in diabetic rats, and this effect may be associated with changes in serum metabolites such as L-NIL, Gln_Cys_Asp, and Geshoidin.

Atherosclerosis risk is elevated in diabetic patients, but the underlying mechanism such as the involvement of macrophages remains unclear. Here, we investigated the underlying mechanism related to the pro-inflammatory activation of macrophages in the development of diabetic atherosclerosis. Bioinformatics tools were used to analyze the macrophage-related transcriptome differences in patients with atherosclerosis and diabetic mice. LDLR −/− mice with DDIT4 depletion were generated and fed a Western diet to induce atherosclerosis. DDIT4 expression was elevated in diabetic mice and patients with atherosclerosis. Macrophage proinflammatory factors F4/80, Il-6, and TNFα were reduced in DDIT4 −/− LDLR −/− mice and necrotic areas were decreased in the aortic root. Atherosclerotic plaque stability was increased in DDIT4 −/− LDLR −/− mice, as evidenced by increased collagen and smooth muscle cell content. DDIT4, regulated by ETV5, acted on macrophages, affecting lipid accumulation, migration capacity, and pro-inflammatory responses. Knockdown of ETV5 increased expression of DDIT4 and pro-inflammatory factors in macrophages, increased necrotic core area in the aortic root, and decreased stability of atherosclerotic plaques in mice, which was abated by DDIT4 knockdown. The findings provide new insight into how diabetes promotes atherosclerosis and support a model wherein loss of ETV5 sustains transcription of DDIT4 and the pro-inflammatory activation of macrophages.

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of O-GlcNAc signaling, in the evolution of diabetic atherosclerosis remains elusive. The goal of this study was to determine whether smooth muscle OGT (smOGT) plays a direct role in hyperglycemia-induced atherosclerotic lesion formation and SMC de-differentiation. Using tamoxifen-inducible Myh11-CreERT2 and Ogtfl/fl mice, we generated smOGTWT and smOGTKO mice, with and without ApoE-null backgrounds. Following STZ-induced hyperglycemia, smOGTWT and smOGTKO mice were kept on a standard laboratory diet for the study duration. In a parallel study, smOGTWTApoE-/- and smOGTKOApoE-/- were initiated on Western diet at 8-wks-age. Animals harvested at 14–16-wks-age were used for plasma and tissue collection. Loss of smOGT augmented SM contractile marker expression in aortic vessels of STZ-induced hyperglycemic smOGTKO mice. Consistently, smOGT deletion attenuated atherosclerotic lesion lipid burden (Oil red O), plaque area (H&E), leukocyte (CD45) and smooth muscle cell (ACTA2) abundance in Western diet-fed hyperglycemic smOGTKOApoE-/- mice. This was accompanied by increased SM contractile markers and reduced inflammatory and proliferative marker expression. Further, smOGT deletion attenuated YY1 and SRF expression (transcriptional regulators of SM contractile genes) in hyperglycemic smOGTKOApoE-/- and smOGTKO mice. These data uncover an athero-protective outcome of smOGT loss-of-function and suggest a direct regulatory role of OGT-mediated O-GlcNAcylation in VSMC de-differentiation in hyperglycemia.

Rescuing endothelial cells from pyroptotic cell death emerges as a potential therapeutic strategy to combat diabetic atherosclerosis. Salvianolic acid A (SAA) is a major water-soluble phenolic acid in the Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine (TCM) and health food products for a long time. This study investigated whether SAA-regulated pyruvate kinase M2 (PKM2) functions to protect endothelial cells. In streptozotocin (STZ)-induced diabetic ApoE −/− mice subjected to a Western diet, SAA attenuated atherosclerotic plaque formation and inhibited pathological changes in the aorta. In addition, SAA significantly prevented NLRP3 inflammasome activation and pyroptosis of endothelial cells in the diabetic atherosclerotic aortic sinus or those exposed to high glucose. Mechanistically, PKM2 was verified to be the main target of SAA. We further revealed that SAA directly interacts with PKM2 at its activator pocket, inhibits phosphorylation of Y105, and hinders the nuclear translocation of PKM2. Also, SAA consistently decreased high glucose-induced overproduction of lactate and partially lactate-dependent phosphorylation of PKR (a regulator of the NLRP3 inflammasome). Further assay on Phenylalanine (PKM2 activity inhibitor) proved that SAA exhibits the function in high glucose-induced pyroptosis of endothelial cells dependently on PKM2 regulation. Furthermore, an assay on c16 (inhibitor of PKR activity) with co-phenylalanine demonstrated that the regulation of the phosphorylated PKR partially drives PKM2-dependent SAA modulation of cell pyroptosis. Therefore, this article reports on the novel function of SAA in the pyroptosis of endothelial cells and diabetic atherosclerosis, which provides important insights into immunometabolism reprogramming that is important for diabetic cardiovascular disease complications therapy.

Diabetes is a major risk factor for cardiovascular disease. However, the exact mechanism by which diabetes contributes to vascular damage is not fully understood. The aim of this study was to investigate the role of SUMO-1 mediated SERCA2a SUMOylation in the development of atherosclerotic vascular injury associated with diabetes mellitus.  ApoE −/− mice were treated with streptozotocin (STZ) injection combined with high-fat feeding to simulate diabetic atherosclerosis and vascular injury. Human aortic vascular smooth muscle cells (HAVSMCs) were treated with high glucose (HG, 33.3 mM) and palmitic acid (PA, 200 µM) for 24 h to mimic a model of diabetes-induced vascular injury in vitro. Aortic vascular function, phenotypic conversion, migration, proliferation, intracellular Ca 2+ concentration, the levels of small ubiquitin-like modifier type 1 (SUMO1), SERCA2a and SUMOylated SERCA2a were detected. Diabetes-induced atherosclerotic mice presented obvious atherosclerotic plaques and vascular injury, companied by significantly lower levels of SUMO1 and SERCA2a in aorta. HG and PA treatment in HAVSMCs reduced the expressions of SUMO1, SERCA2a and SUMOylated SERCA2a, facilitated the HAVSMCs phenotypic transformation, proliferation and migration, attenuated the Ca 2+ transport, and increased the resting intracellular Ca 2+ concentration. We also confirmed that SUMO1 directly bound to SERCA2a in HAVSMCs. Overexpression of SUMO1 restored the function and phenotypic contractile ability of HAVSMCs by upregulating SERCA2a SUMOylation, thereby alleviating HG and PA-induced vascular injury. These observations suggest an essential role of SUMO1 to protect diabetes-induced atherosclerosis and aortic vascular injury by the regulation of SERCA2a-SUMOylation and calcium homeostasis. Graphic abstract

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.

Background Diabetic atherosclerosis is one of the main causes of morbidity and mortality worldwide, but its therapeutic options are limited. Liraglutide (LIR), a synthetic analog of GLP-1 approved as an anti-obesity drug by the FDA, has been reported as a promising drug for diabetic atherosclerosis. However, the main problem with LIR is its use that requires regular parenteral injections, which necessitates the improvement of drug delivery for increased efficiency and minimization of injection numbers. Results The objective of our present study was to prepare and characterize nanoparticles (BSA@LIR-PMF) for targeted drug delivery using LIR-encapsulated platelet membrane fragments (PMF) coated bovine serum albumin (BSA). We used various methods to characterize the prepared nanoparticles and evaluated their efficiency on diabetes-induced atherosclerosis in vitro and in vivo. The results showed that the nanoparticles were spherical and had good stability and uniform size with intact membrane protein structure. The loading and encapsulation rates (LR and ER) of BSA@LIR-PMF were respectively 8.29% and 90.39%, while the cumulative release rate was around 77.06% after 24 h. Besides, we also examined the impact of BSA@LIR-PMF on the proliferation, migration, phagocytosis, reactive oxygen species (ROS) levels, oxidative phosphorylation, glycolysis, lactate and ATP levels, and lipid deposition in the aortas. The results indicated that BSA@LIR-PMF could effectively inhibit ox-LDL-stimulated abnormal cell proliferation and migration, reduce the level of ROS and lactate concentration, and enhance the level of ATP, thereby improving oxidative phosphorylation in ox-LDL-treated cells. Conclusion BSA@LIR-PMF significantly inhibited diabetes-induced atherosclerosis. It was anticipated that the BSA@LIR-PMF nanoparticles might be used for treating diabetes-associated cardiovascular complications.

Mulberry leaf (Morus alba L.) has been used as a health food and in traditional medicine to treat several metabolic diseases, including diabetes, hypertension, and hyperlipidemia. However, the mechanism by which mulberry leaf and its functional components mediate atherosclerosis remains unclear. This study aimed to determine the effect of mulberry leaf extract (MLE) and its major component, neochlorogenic acid (nCGA), on the proliferation and migration of rat aortic vascular smooth muscle cells (VSMCs, A7r5 cell line) under diabetic cultured conditions (oleic acid and high glucose, OH). Our findings showed that MLE and nCGA significantly inhibited cell proliferation and migration in A7r5 cells as determined by a scratch wound assay and a Transwell assay. Furthermore, we observed MLE and nCGA inhibited cell proliferation and migration, such as reducing the phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt), focal adhesion kinase (FAK), and small GTPase proteins using Western blot analysis. In conclusion, we confirmed the anti-atherosclerotic effects of MLE and nCGA in reducing vascular smooth muscle cell (VSMC) migration and proliferation under diabetic cultured conditions via inhibition of FAK/small GTPase proteins, PI3K/Akt, and Ras-related signaling.

Evidence suggests that macrophage pyroptosis promotes the progression of diabetic atherosclerosis. Spermine, a natural cellular metabolite, demonstrates a protective effect against cardiovascular diseases. However, whether spermine has a protective effect against macrophage pyroptosis caused by high glucose (HG) and oxidized low-density lipoprotein (ox-LDL) conditions remains to be elucidated. To investigate the protective effect of spermine and the related underlying mechanism, THP-1 macrophages were treated with HG/ox-LDL, spermine, or the specific nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. Cell viability was detected using CCK-8, cell membrane permeability was analyzed using lactate dehydrogenase (LDH) and Hoechst/propidium iodide staining and pyroptosis-related gene and protein expression levels were evaluated using polymerase chain reaction and western blot analysis. Spermine showed a potent preventive effect on THP-1 macrophage pyroptosis and oxidative stress induced by HG/ox-LDL. Cells treated with spermine showed increased cell viability, reduced reactive oxygen species (ROS) production, decreased LDH levels in the supernatant and reduced cell swelling. In addition, spermine significantly reduced NLR family pyrin domain containing 3, cleaved caspase-1, N-gasdermin D and IL-1β expression, as well as IL-1β levels in the supernatant. This demonstrated that the inhibition of pyroptosis and oxidative stress due to spermine was Nrf2 dependent. Furthermore, spermine enhanced Nrf2 nuclear translocation, thereby increasing heme oxygenase-1 and NADPH quinone oxidoreductase-1 expression, which subsequently reduced ROS production. In addition, the anti-pyroptotic and antioxidant effects of spermine were reversed by ML385 inhibition of Nrf2. It was concluded that spermine prevented macrophage pyroptosis and increased ROS overproduction by activating the Nrf2 pathway. The data suggested that spermine may be a potential novel drug for the treatment of diabetic atherosclerosis because it targets macrophage pyroptosis.