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Pyroptosis is associated with various cardiovascular diseases. Increasing evidence suggests that long noncoding RNAs (lncRNAs) have been implicated in gene regulation, but how lncRNAs participate in the regulation of pyroptosis in the heart remains largely unknown. In this study, we aimed to explore the antipyroptotic effects of lncRNA FGF9-associated factor (FAF) in acute myocardial infarction (AMI). The expression patterns of lncRNA FAF, miR-185-5p and P21 activated kinase 2 (PAK2) were detected in hypoxia/ischaemia-induced cardiomyocytes. Hoechst 33342/PI staining, lactate dehydrogenase (LDH) release assay, immunofluorescence and Western blotting were conducted to assay cell pyroptosis. The interaction between lncRNA FAF, miR-185-5p and PAK2 was verified by bioinformatics analysis, small RNA sequencing luciferase reporter assay and qRT-PCR. The expression of LncRNA FAF was downregulated in hypoxic cardiomyocytes and myocardial tissues. Overexpression of lncRNA FAF could attenuate cardiomyocyte pyroptosis, improve cell viability and reduce infarct size during the procession of AMI. Moreover, lncRNA FAF was confirmed as a sponge of miR-185-5p and promoted PAK2 expression in cardiomyocytes. Collectively, our findings reveal a novel lncRNA FAF/miR-185-5p/PAK2 axis as a crucial regulator in cardiomyocyte pyroptosis, which might be a potential therapeutic target of AMI.

The dysregulation of Long noncoding RNAs (lncRNAs) has been implicated in many cardiovascular diseases, including cardiac fibrosis. However, the functions and mechanisms of lncRNAs in cardiac fibroblasts (CFs) have not been fully elucidated. First, we observed a correlation between cardiac remodeling (CR) and lncRNA FAF (FGF9-associated factor, termed FAF) expression in the heart. In vitro, we found that the expression of lncRNA FAF was altered in CFs, whereas it behaved inconsistently in cardiomyocytes (CMs). Next, we investigated the effects of lncRNA FAF on angiotensinogen II (Ang II)-induced cardiac fibrosis in neonatal rat CFs and explored the mechanism underlying these effects. In this study, lncRNA FAF was enriched in CFs and was associated with cardiac fibrosis. Upregulation of lncRNA FAF significantly restrained Ang II-induced increases in cell proliferation, differentiation and collagen accumulation of CFs. Moreover, we found that the function of lncRNA FAF was mainly realized through Transforming growth factor β1 (TGFβ1) secretion and then downregulated phosphorylation of Smad2/3. Additional analysis revealed that Fibroblast growth factor 9 (FGF9) is a direct target of lncRNA FAF, as the overexpression of lncRNA FAF could increase the expression of FGF9 and knockdown of the FGF9 expression could attenuate the down-regulation of lncRNA FAF on TGFβ1-P-Smad2/3 pathway. Furthermore, knockdown of the FGF9 expression also abolished the inhibitory effect of FAF on fibrosis. In summary, we demonstrated that the overexpression of lncRNA FAF could inhibit fibrosis induced by Ang II via the TGFβ1-P-Smad2/3 signalling by targeting FGF9 in CFs.

Background The pericoronary fat attenuation index (FAI) is assessed using standard coronary computed tomography angiography, and it has emerged as a novel imaging biomarker of coronary inflammation. The present study assessed whether increased pericoronary FAI values on coronary computed tomography angiography were associated with vulnerable plaque components and their intracellular cytokine levels in patients with non‐ST elevation acute coronary syndrome. Methods and Results A total of 195 lesions in 130 patients with non‐ST elevation acute coronary syndrome were prospectively included. Lesion‐specific pericoronary FAI, plaque components and other plaque features were evaluated by coronary computed tomography angiography. Local T cell subsets and their intracellular cytokine levels were detected by flow cytometry. Lesions with pericoronary FAI values >−70.1 Hounsfield units exhibited spotty calcification (43.1% versus 25.0%, P =0.015) and low‐attenuation plaques (17.6% versus 4.2%, P =0.016) more frequently than lesions with lower pericoronary FAI values. Further quantitative plaque compositional analysis showed that increased necrotic core volume (Pearson’s r=0.324, P P P Conclusions The pericoronary FAI may be a reliable indicator of local immune‐inflammatory response activation, which is closely related to plaque vulnerability. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04792047.

Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine‐protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation– induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte‐specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain‐ and loss‐of‐function experiments using cardiomyocyte‐specific adeno‐associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK‐3β (glycogen synthase kinase‐3β) activity and upregulating β‐catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S‐specific cyclin‐D1, c‐myc (cellular‐myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

Abnormalities in programmed cell death (PCD) signaling cascades can be observed in the development and progression of various cardiovascular diseases, such as apoptosis, necrosis, pyroptosis, ferroptosis, and cell death associated with autophagy. Aberrant activation of PCD pathways is a common feature leading to excessive cardiac remodeling and heart failure, involved in the pathogenesis of various cardiovascular diseases. Conversely, timely activation of PCD remodels cardiac structure and function after injury in a spatially or temporally restricted manner and corrects cardiac development similarly. As many cardiovascular diseases exhibit abnormalities in PCD pathways, drugs that can inhibit or modulate PCD may be critical in future therapeutic strategies. In this review, we briefly describe the process of various types of PCD and their roles in the occurrence and development of cardiovascular diseases. We also discuss the interplay between different cell death signaling cascades and summarize pharmaceutical agents targeting key players in cell death signaling pathways that have progressed to clinical trials. Ultimately a better understanding of PCD involved in cardiovascular diseases may lead to new avenues for therapy.

Background: High D-dimer (DD) is associated with short-term adverse outcomes in patients with acute coronary syndrome (ACS). In ACS patients who underwent percutaneous coronary intervention (PCI), however, the value of DD (or combined with neutrophil to lymphocyte ratio [NLR]) to predict long-term major adverse cardiovascular events (MACEs) has not been fully evaluated. Methods: Patients diagnosed with ACS and receiving PCI were included. The primary outcome was MACEs. Cox proportional hazards regression and logistic regression was used to illustrate the relationship between clinical risk factors, biomarkers and MACEs. Survival models were developed based on significant factors and evaluated by the Concordance-index (C-index). Results: The final study cohort was comprised of 650 patients (median age, 64 years; 474 males), including 98 (15%) with MACEs during a median follow-up period of 40 months. According to the cut-off value of DD and NLR, the patients were separated into four groups: high DD or nonhigh DD with high or nonhigh NLR. After adjusting for confounding variables, DD (adjusted hazard ratio [aHR]: 2.39, 95% confidence interval [CI]: 1.52–3.76) and NLR (aHR: 2.71, 95% CI: 1.78–4.11) were independently associated with long-term MACEs. Moreover, patients with both high DD and NLR had a significantly higher risk in MACEs when considering patients with nonhigh DD and NLR as reference (aHR: 6.19, 95% CI: 3.30–11.61). The area under curve (AUC) increased and reached 0.70 in differentiating long-term MACEs when DD and NLR were combined, and survival models incorporating the two exhibited a stronger predictive power (C-index: 0.75). Conclusions: D-dimer (or combined with NLR) can be used to predict long-term MACEs in ACS patients undergoing PCI.

Adult mammals have limited potential for cardiac regeneration after injury. In contrast, neonatal mouse heart, up to 7 days post birth, can completely regenerate after injury. Therefore, identifying the key factors promoting the proliferation of endogenous cardiomyocytes (CMs) is a critical step in the development of cardiac regeneration therapies. In our previous study, we predicted that mitogen-activated protein kinase (MAPK) interacting serine/threonine-protein kinase 2 (MNK2) has the potential of promoting regeneration by using phosphoproteomics and iGPS algorithm. Here, we aimed to clarify the role of MNK2 in cardiac regeneration and explore the underlying mechanism. In vitro, MNK2 overexpression promoted, and MNK2 knockdown suppressed cardiomyocyte proliferation. In vivo, inhibition of MNK2 in CMs impaired myocardial regeneration in neonatal mice. In adult myocardial infarcted mice, MNK2 overexpression in CMs in the infarct border zone activated cardiomyocyte proliferation and improved cardiac repair. In CMs, MNK2 binded to eIF4E and regulated its phosphorylation level. Knockdown of eukaryotic translation initiation factor (eIF4E) impaired the proliferation-promoting effect of MNK2 in CMs. MNK2-eIF4E axis stimulated CMs proliferation by activating cyclin D1. Our study demonstrated that MNK2 kinase played a critical role in cardiac regeneration. Over-expression of MNK2 promoted cardiomyocyte proliferation in vitro and in vivo, at least partly, by activating the eIF4E-cyclin D1 axis. This investigation identified a novel target for heart regenerative therapy.

Calcific aortic valve disease (CAVD) is characterized by progressive mineralization of the aortic valve. Lipid infiltration and oxidative stress are the driving forces for the initiation and development of this disease. However, it remains unknown whether oxidized high-density lipoprotein (ox-HDL) plays a role in the mineralization of aortic valve interstitial cells (AVICs). Serum ox-HDL levels were determined in 168 severe CAVD patients and 168 age- and gender-matched non-CAVD controls. Results showed that ox-HDL concentrations were significantly increased in CAVD compared with the control group (131.52 ± 30.96 ng/mL vs. 112.58 ± 32.20 ng/mL, P

Background: Emerging studies have described and analyzed epidemiological, clinical, laboratory, and radiological features of COVID-19 patients. Yet, scarce information is available regarding the association of lipid profile features and disease severity and mortality.Methods: We conducted a prospective observational cohort study to investigate lipid profile features in patients with COVID-19. From 9 February to 4 April 2020, a total of 99 patients (31 critically ill and 20 severely ill) with confirmed COVID-19 were included in the study. Dynamic alterations in lipid profiles were recorded and tracked. Outcomes were followed up until 4 April 2020.Results: We found that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apoA-1) levels were significantly lower in the severe disease group, with mortality cases showing the lowest levels (p < 0.0001). Furthermore, HDL-C and apoA-1 levels were independently associated with disease severity (apoA-1: odds ratio (OR): 0.651, 95% confidence interval (CI): 0.456–0.929, p = 0.018; HDL-C: OR: 0.643, 95% CI: 0.456–0.906, p = 0.012). For predicting disease severity, the areas under the receiver operating characteristic curves (AUCs) of HDL-C and apoA-1 levels at admission were 0.78 (95% CI, 0.70–0.85) and 0.85 (95% CI, 0.76–0.91), respectively. For in-hospital deaths, HDL-C and apoA-1 levels demonstrated similar discrimination ability, with AUCs of 0.75 (95% CI, 0.61–0.88) and 0.74 (95% CI, 0.61–0.88), respectively. Moreover, patients with lower serum concentrations of apoA-1 (p < 0.001). Notably, levels of apoA-1 and HDL-C were inversely proportional to disease severity. The survivors of severe cases showed significant recovery of apoA-1 levels at the end of hospitalization (vs. midterm apoA-1 levels, p = 0.02), whereas the mortality cases demonstrated continuously lower apoA-1 levels throughout hospitalization. Correlation analysis revealed that apoA-1 and HDL-C levels were negatively correlated with both admission levels and highest concentrations of C-reactive protein and interleukin-6.Conclusions: Severely ill COVID-19 patients featured low HDL-C and apoA-1 levels, which were strongly correlated with inflammatory states. Thus, low apoA-1 and HDL-C levels may be promising predictors for severe disease and in-hospital mortality in patients suffering from COVID-19.

Background Increasing evidence showed that carbamylated lipoprotein accelerated atherosclerosis. However, whether such modification of high-density lipoprotein (HDL) particles alters in type 2 diabetes mellitus (T2DM) patients and facilitates vascular complications remains unclear. We aimed to investigate the alteration of the carbamylation in HDL among T2DM patients and clarify its potential role in atherogenesis. Methods A total of 148 consecutive T2DM patients undergoning angiography and 40 age- and gender-matched control subjects were included. HDL was isolated from plasma samples, and the concentration of HDL carbamyl-lysine (HDL-CBL) was measured. Furthermore, the HDL from subjects and in-vitro carbamylated HDL (C-HDL) was incubated with endothelial cells and monocyte to endothelial cell adhesion. Adhesion molecule expression and signaling pathway were detected. Results Compared with the control group, the HDL-CBL level was remarkably increased in T2DM patients (6.13 ± 1.94 vs 12.00 ± 4.06 (ng/mg), P P = 0.001). Multivariate logistic regression analysis demonstrated that higher HDL-CBL level was independently associated with a higher prevalence of CAD in diabetic patients after adjusting for established cofounders (adjusted odds ratio 1.174, 95% confidence Interval 1.045–1.319, p = 0.017). HDL from diabetic patients with CAD enhanced greater monocyte adhesion than that from the non-CAD or the control group (P Conclusions Our study identified elevated carbamylation modification of HDL from T2DM patients, especially in those with concomitant CAD. We also evidenced that C-HDL enhanced monocyte to endothelial cell adhesion, indicating a potential pro-atherogenic role of C-HDL in atherosclerosis among T2DM patients. Trial registrationhttps://register.clinicaltrials.gov, NCT04390711 Registered on 14 May 2020; Retrospectively registered

Long noncoding RNAs (lncRNAs) have been increasingly considered to play an important role in the pathological process of various cardiovascular diseases, which often bind to the proximal promoters of the protein-coding gene to regulate the protein expression. However, the functions and mechanisms of lncRNAs in cardiomyocytes have not been fully elucidated. High-throughput RNA sequencing was performed to identify the differently expressed lncRNAs and messenger RNAs (mRNAs) between acute myocardial infarction (AMI) rats and healthy controls. One novel lncRNA FGF9-associated factor (termed FAF) and mRNAs in AMI rats were verified by bioinformatics, real-time polymerase chain reaction or western blot. Moreover, RNA fluorescence in situ hybridization was performed to determine the location of lncRNA. Subsequently, a series of in vitro assays were used to observe the functions of lncRNA FAF in cardiomyocytes. The expression of lncRNA FAF and FGF9 were remarkably decreased in ischemia-hypoxia cardiomyocytes and heart tissues of AMI rats. Overexpression of FAF could significantly inhibit cardiomyocytes apoptosis induced by ischemia and hypoxia. Conversely, knockdown of lncRNA FAF could promote apoptosis in ischemia-hypoxia cardiomyocytes. Moreover, overexpression of lncRNA FAF could also increase the expression of FGF9. Knockdown of the FGF9 expression could promote apoptosis in cardiomyocytes with the insult of ischemia and hypoxia, which was consistent with the effect of lncRNA FAF overexpression on cardiomyocyte apoptosis. Mechanistically, FGF9 inhibited cardiomyocytes apoptosis through activating signaling tyrosine kinase FGFR2 via phosphoinositide 3-kinase/protein kinase B signaling pathway. Thus, lncRNA FAF plays a protective role in ischemia-hypoxia cardiomyocytes and may serve as a treatment target for AMI.

Xiu-juan Gai,1,2 Yu-mei Wei,2 Heng-min Tao,1,2 Dian-zheng An,2 Jia-teng Sun,1,2 Bao-sheng Li2 1School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 2Department of Radiation Oncology VI, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China Purpose: This study was designed to compare the survival outcomes of temozolomide-based chemoradiotherapy (TMZ + RT) vs radiotherapy alone (RT-alone) for low-grade gliomas (LGGs) after surgical resection. Patients and methods: In this retrospective analysis, we reviewed postoperative records of 69 patients with LGGs treated with TMZ + RT (n=31) and RT-alone (n=38) at the Shandong Cancer Hospital Affiliated to Shandong University between June 2011 and December 2013. Patients in the TMZ + RT group were administered 50–100 mg oral TMZ every day until the radiotherapy regimen was completed. Results: The median follow-up since surgery was 33 months and showed no significant intergroup differences (P=0.06). There were statistically significant intergroup differences in the progression-free survival rate (P=0.037), with 83.9% for TMZ-RT group and 60.5% for RT-alone group. The overall 2-year overall survival (OS) rate was 89.86%. Age distribution (≥45 years and

It is thought that carbamylated modification plays a crucial role in the development and progression of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). However, information on the biological effects of carbamylated high-density lipoprotein (C-HDL) in ESRD is poor. The present study investigated the carbamylation level of HDL in ESRD and the effects of C-HDL on endothelial repair properties. HDL was isolated from healthy control subjects ( n = 22) and patients with ESRD ( n = 30). The carbamylation level of HDL was detected using ELISA. Isolated C-HDL for use in tissue culture experiments was carbamylated in vitro to a similar extent to that observed in ESRD. Human arterial endothelial cells were treated with C-HDL or native HDL to assess their migration, proliferation, and angiogenesis properties. HDL-associated paraoxonase 1 activity was also determined by spectrophotometry assay. Compared with healthy control subjects, the carbamylation level of HDL in ESRD patients was increased and positively correlated with blood urea concentration. In vitro, C-HDL significantly inhibited migration, angiogenesis, and proliferation in endothelial cells. Mechanistic studies revealed that HDL-associated paraoxonase 1 activity was decreased and negatively correlated with the carbamylation level of HDL in ESRD patients. In addition, C-HDL suppressed the expression of VEGF receptor 2 and scavenger receptor class B type I signaling pathways in endothelial cells. In conclusion, the present study identified a significantly increased carbamylation level of HDL in ESRD. Furthermore, C-HDL inhibited endothelial cell repair functions.

Aims Impaired anti-inflammatory ability of high-density lipoprotein (HDL) has been demonstrated in patients with type-2 diabetes mellitus (T2DM). However, whether HDL from patients with diabetic nephropathy (DN) suffers additional damage remains unknown. This study compared the anti-inflammatory capacities of HDL from healthy controls, T2DM patients with normal renal function, and T2DM patients with DN. Materials and methods HDL was isolated from healthy controls (n=33) and T2DM patients with normal renal function (n=21), chronic kidney disease (CKD) (n=27), and end-stage renal disease (ESRD) (n=27). Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers were pretreated with HDL (100μg/mL) for 1h, then incubated with lipopolysaccharide (LPS) (50ng/mL) for 24h. The anti-inflammatory ability of HDL was measured as the secretion of TNF-α in LPS-activated monocytes. Results The anti-inflammatory ability of HDL was gradually impaired as kidney function declined. Serum amyloid A (SAA) concentration in HDL DN significantly increased and was positively correlated with the impaired anti-inflammatory ability of HDL (Pearson r=0.315, P=0.006). Furthermore, HDL supplemented with SAA significantly increased TNF-α release from PBMCs compared with that from control HDL. Conclusions These findings identified an impaired anti-inflammatory capacity of HDL from DN patients, which might be attributable to SAA enrichment.

Background Cyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear. Methods and Results In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind‐limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate‐treated mice. Likewise, there were fewer capillaries in the ischemic hind‐limb tissue of cyanate‐exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube‐formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3‐kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09±13.08 versus 15.54±9.02 ng/mL, P =0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth. Conclusions Impaired angiogenesis induced by cyanate might contribute to poor coronary collateral growth.

Although high-density lipoprotein (HDL) can exhibit anti-inflammatory properties, these potent activities can become deficient and even transform into proinflammatory effects under various pathophysiological states. We investigated the effect of diabetic HDL on the inflammatory response in human monocytes and its relation to the existence of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM). HDL was isolated from DM patients with (n = 61) or without (n = 31) CAD (diameter stenosis ≥50%) and healthy controls (n = 40). Human peripheral blood mononuclear cells were incubated with HDL and the proinflammatory ability of HDL was determined by tumor necrosis factor-α (TNF-α) secretion in peripheral blood mononuclear cells. Secretion of TNF-α in human monocytes in response to diabetic HDL was significantly increased compared with that of the control HDL. Of note, HDL from DM patients with CAD stimulated the release of TNF-α in monocytes to a greater extent than that of HDL from those without CAD. Multiple linear regression analysis showed that the proinflammatory ability of HDL was independently associated with diabetes duration, hemoglobin A1c, serum levels of high-sensitivity C-reactive protein (hs-CRP) and reduced glomerular filtration rate (GFR). Furthermore, the proinflammatory ability of HDL was a significant predictor for the presence of CAD in patients with DM.

Background: ApoA-IV is associated with HDL in plasma but a large portion circulates lipid free. It has been shown to possess anti-inflammatory and anti-atherosclerotic effects. Methods and Results: We isolated HDL from plasma of type 2 diabetic patients and healthy controls, and found that apoA-IV of HDL from diabetic patients was significantly glycated by using Western blot and mass spectrometry. The glycation levels of apoA-IV were higher in diabetic patients than in controls, and were associated with the severity of coronary artery disease. Immunohistochemically, glycation sites co-localized with apoA-IV in atherosclerotic plaques from diabetic patients. In cell and animal studies, in vitro glycated apoA-IV protein promoted inflammatory reactions in human aortic endothelial cells and atherogenesis in apoE-KO mice as compared with control, whereas apoA-IV exhibited anti-inflammatory and anti-atherogenic effects. The pro-inflammatory action of glycated apoA-IV was mediated by receptor for glycation end products in endothelial cells. In microarray analysis and verification in endothelial cells, glycated apoA-IV but not apoA-IV, enhanced the expression of nuclear receptor NR4A3 greatly. Glycated apoA-IV-induced inflammatory reaction and atherogenic effect was significantly attenuated in endothelial cell with siRNA-NR4A3, native endothelial cells and macrophages from NR4A3-KO mice and in NR4A3-KO mice. Co-localization of NR4A3 with CD31 was observed in atherosclerotic plaque from diabetic patients. Moreover, glycated apoA-IV but not apoA-IV induced trans-activation of NR4A3 to the promoter of adhesion molecules (VCAM-1, ICAM-1 and E-selectin). ESI-Q-TOF-MS identified several glycation sites including K78, K189 and K328 in apoA-IV from diabetic patients, but not in controls. Mutated apoA-IV proteins (m-apoA-IV-K78A/K189A/K328A) were made. In vitro glycated m-apoA-IV displayed significantly attenuated activation of NR4A3 in endothelial cells and atherogenesis in apoE-KO mice, as compared with glycated apoA-IV. Conclusion: Glycation of apoA-IV is associated with the severity of coronary artery disease in diabetic patients and glycated apoA-IV protein promotes atherogenesis through nuclear receptor NR4A3 mediation.

Objective To investigate whether apolipoprotein A (apoA)-I glycation and paraoxonase (PON) activities are associated with the severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Methods Relative intensity of apoA-I glycation and activities of high-density lipoprotein (HDL)-associated PON1 and PON3 were determined in 205 consecutive T2DM patients with stable angina with (n = 144) or without (n = 61) significant CAD (luminal diameter stenosis ≥ 70 %). The severity of CAD was expressed by number of diseased coronary arteries, extent index, and cumulative coronary stenosis score (CCSS). Results The relative intensity of apoA-I glycation was higher but the activities of HDL-associated PON1 and PON3 were lower in diabetic patients with significant CAD than in those without. The relative intensity of apoA-I glycation increased but the activities of HDL-associated PON1 and PON3 decreased stepwise from 1 - to 3 - vessel disease patients (P for trend

To evaluate whether glycation of high-density lipoprotein (HDL) increases cardiovascular risk in patients with type 2 diabetes mellitus by altering its anti-atherogenic property.Data cited in this review were obtained mainly from Pubmed and Medline in English from 2000 to 2013, with keywords "glycation", "HDL", and "atherosclerosis". Study selection Articles regarding glycation of HDL and its role in atherogenesis in both humans and experimental animal models were identified, retrieved and reviewed.Glycation alters the structure of HDL and its associated enzymes, resulting in an impairment of atheroprotective functionality and increased risks for cardiovascular events in type 2 diabetic patients.Glycation of HDL exerts a deleterious effect on the development of cardiovascular complications in diabetes.