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BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with angina symptoms and adverse clinical outcomes in patients without obstructive coronary artery disease (CAD). Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is reportedly a marker of the initiation and acceleration of epicardial coronary atherosclerosis. However, its impact on CMD remains unclear. OBJECTIVE: We aimed to investigate the relationship between CMD and MDA-LDL levels. METHODS: This study included 95 patients who did not receive lipid-lowering medications and had no obstructive CAD. Obstructive CAD was defined as >50 % diameter reduction on coronary angiography or fractional flow reserve of ≤0.80. We retrospectively analyzed coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and MDA-LDL levels. CMD was defined as either CFR <2.0 or IMR ≥25. RESULTS: CMD was observed in 29 (31 %) patients. MDA-LDL levels were significantly higher in patients with CMD than in those without CMD (124.8 ± 37.6 vs. 95.3 ± 29.5 U/L; p < 0.01). Univariable logistic regression analysis indicated a significant relationship between CMD and MDA-LDL levels (odds ratio (OR): 1.03; p < 0.01). In the multivariable model, MDA-LDL levels were significantly associated with CMD (OR: 1.02; p < 0.01). Regression analysis showed a significant correlation between MDA-LDL levels and CFR (r = -0.42, p < 0.01) and IMR (r = 0.35, p < 0.01). In the multiple regression analysis, MDA-LDL levels were independently associated with CFR (ß = -0.30, p < 0.01) and IMR (ß = 0.26, p = 0.02). CONCLUSION: MDA-LDL levels were associated with CMD in patients without obstructive CAD.

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Background and Objectives: Peripheral arterial stiffness (PAS), assessed by brachial-ankle pulse wave velocity (baPWV), is an independent biomarker of cardiovascular diseases (CVD) in patients on maintenance hemodialysis (HD). Malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker, has been linked to atherosclerosis and CVD. However, the association between serum MDA-LDL and PAS among HD patients has not been fully elucidated. This study aimed to examine the association of serum MDA-LDL with PAS in HD patients and to identify the optimal cutoff value of serum MDA-LDL for predicting PAS. Materials and Methods: A cross-sectional study was conducted in 100 HD patients. Serum MDA-LDL was quantified using an enzyme-linked immunosorbent assay (ELISA), and baPWV was measured using a volume plethysmographic device. Patients were divided into the PAS group (baPWV > 18.0 m/s) and the non-PAS group (baPWV ≤ 18.0 m/s). The associations of baPWV and other clinical and biochemical parameters with serum MDA-LDL were assessed by multivariable logistic regression analyses. A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff value of serum MDA-LDL for predicting PAS. Results: In multivariable logistic regression analysis, higher serum MDA-LDL, older age, and higher serum C-reactive protein [odds ratios (ORs) and 95% confidence intervals: 1.014 (1.004-1.025), 1.044 (1.004-1.085) and 3.697 (1.149-11.893)] were significantly associated with PAS. In the ROC curve analysis, the optimal cutoff value of MDA-LDL for predicting PAS was 80.91 mg/dL, with a sensitivity of 79.25% and a specificity of 59.57%. Conclusions: Greater serum MDA-LDL levels, particularly ≥80.91 mg/dL, were independently associated with PAS in HD patients. The findings suggest that oxidative stress plays a crucial role in the pathogenesis of PAS, and targeting MDA-LDL may be a potential therapeutic strategy for reducing cardiovascular risk in HD patients.

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The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation.

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Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.

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The simultaneous detection of atherosclerotic cardiovascular disease (ACSVD) biomarkers was recently of great scientific interest. In this work, magnetic beads-based immunosensors for the simultaneous detection of low density lipoprotein (LDL) and malondialdehyde-modified low density lipoprotein (MDA-LDL) were presented. The approach proposed was based on the formation of two types of specific immunoconjugates consisting of monoclonal antibodies: anti-LDL or anti-MDA-LDL, together with redox active molecules: ferrocene and anthraquinone, respectively, coated on magnetic beads (MBs). The decrease in redox agent current in the concentration range: 0.001-1.0 ng/mL for LDL and 0.01-10.0 ng/mL for MDA-LDL, registered by square wave voltammetry (SWV), was observed upon the creation of complex between LDL or MDA-LDL and appropriate immunoconjugates. The detection limits of 0.2 ng/mL for LDL and 0.1 ng/mL for MDA-LDL were estimated. Moreover, the results of selectivity against the possible interferents were good, as human serum albumin (HSA) and high density lipoprotein (HDL), stability and recovery studies demonstrated the potential of platform proposed for early prognosis and diagnosis of ASCVD.

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BACKGROUND: Febuxostat is a selective xanthine oxidase inhibitor that reportedly exhibits antioxidant properties. We previously performed a multicentre, randomized controlled (PRIZE) study for vascular evaluation under uric acid (UA) control by febuxostat to investigate the progression of carotid lesions in asymptomatic hyperuricemic patients with carotid atherosclerosis for 2 years. HYPOTHESIS: The current subanalysis of the PRIZE study aimed to assess the effect of febuxostat on the level of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker. METHODS: We recruited 383 patients (febuxostat group, n = 200; control group, n = 183) from the PRIZE trial for whom MDA-LDL measurements were available. The UA, MDA-LDL, low-density lipoprotein cholesterol (LDL-C) levels, and MDA-LDL/LDL-C ratio were identified, represented as the estimated difference from baseline to 24 months. We also evaluated the relationship between febuxostat dose (10, ≤20 to <40, and ≤40 to ≤60 mg) and changes in the MDA-LDL level, LDL-C level, or MDA-LDL/LDL-C ratios. RESULTS: The estimated change in MDA-LDL/LDL-C ratio from baseline to 24 months was significantly lower in the febuxostat group than in the control group (p = .025), whereas the estimated changes in MDA-LDL (p = .235) and LDL-C (p = .323) levels did not differ between the two groups. No significant correlation existed between the febuxostat doses and the estimated change in the MDA-LDL level (p = .626), LDL-C level (p = .896), or MDA-LDL/LDL-C ratio (p = .747). CONCLUSIONS: Our findings may indicate a possibility that febuxostat can lower the MDA-LDL/LDL-C ratio, a potential marker of atherosclerosis and oxidative stress, in asymptomatic hyperuricemic patients with carotid atherosclerosis. Further studies are required to validate our findings and elucidate the clinical antioxidant effect of febuxostat.

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Astaxanthin (ASTX) is an antioxidant agent. Recently, its use has been focused on the prevention of diabetes and atherosclerosis. We examined the effects of astaxanthin supplementation for 12 weeks on glucose metabolism, glycemic control, insulin sensitivity, lipid profiles and anthropometric indices in healthy volunteers including subjects with prediabetes with a randomized, placebo-controlled trial. METHODS: We enrolled 53 subjects who met our inclusion criteria and administered them with 12 mg astaxanthin or a placebo once daily for 12 weeks. Subsequently, their HbA1c levels, lipid profiles and biochemical parameters were determined. The participants also underwent a 75 g oral glucose tolerance test (OGTT), vascular endothelial function test and measurement of the visceral fat area. RESULTS: After astaxanthin supplementation for 12 weeks, glucose levels after 120 min in a 75 g OGTT significantly decreased compared to those before supplementation. Furthermore, the levels of HbA1c (5.64 ± 0.33 vs. 5.57 ± 0.39%, p < 0.05), apo E (4.43 ± 1.29 vs. 4.13 ± 1.24 mg/dL, p < 0.05) and malondialdehyde-modified low-density lipoprotein (87.3 ± 28.6 vs. 76.3 ± 24.6 U/L, p < 0.05) were also reduced, whereas total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-C (HDL-C) levels were unaltered. The Matuda index, which is one of the parameters of insulin resistance, was improved in the ASTX group compared to that before supplementation. CONCLUSIONS: our results suggest that ASTX may have preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects.

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BACKGROUND: Although elevated levels of oxidized low-density lipoprotein (LDL) could play a critical role in vulnerable plaque, there are no studies that have compared coronary high-intensity plaque (HIP) and circulating malondialdehyde-modified (MDA)-LDL levels for the prediction of cardiac events.Methods and Results:A total of 139 patients with coronary artery stenosis (>70%) were examined with non-contrast T1-weighted magnetic resonance imaging (MRI) (HIP: n=64, non-HIP: n=75). Scheduled percutaneous coronary intervention (PCI) for culprit lesions was performed within 48 h after MRI. HIP was defined as a signal intensity of coronary plaque to cardiac muscle ratio (PMR) ≥1.4. We evaluated the subsequent major adverse cardiac events (MACE) during the follow-up period (5.6±1.3 years). MDA-LDL levels were independently associated with the presence of HIP (P<0.0001). The incidence of MACE was 15%, and it was significantly higher in patients with HIP (27%) than in those without HIP (5%; P=0.011). Cox proportional hazard analysis showed MDA-LDL levels (P=0.007) and PMR (P=0.016) were significantly associated with MACE. For MACE prediction, C-statistic values for MDA-LDL, PMR, and PMR+MDA-LDL were 0.724, 0.791, and 0.800, respectively. Compared with MDA-LDL alone, the addition of PMR to MDA-LDL increased net reclassification improvement by 0.78 (P=0.012). CONCLUSIONS: MDA-LDL levels might be associated with the presence of HIP in patients with coronary artery disease. Furthermore, adding PMR to MDA-LDL levels markedly improved prediction of subsequent MACE after PCI.

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Because atherosclerotic cardiovascular disease is a leading cause of death worldwide, understanding inflammatory processes underpinning its pathology is critical. B cells have been implicated as a key immune cell type in regulating atherosclerosis. B-cell effects, mediated by antibodies and cytokines, are subset specific. In this review, we focus on elaborating mechanisms underlying subtype-specific roles of B cells in atherosclerosis and discuss available human data implicating B cells in atherosclerosis. We further discuss potential B cell-linked therapeutic approaches, including immunization and B cell-targeted biologics. Given recent evidence strongly supporting a role for B cells in human atherosclerosis and the expansion of immunomodulatory agents that affect B-cell biology in clinical use and clinical trials for other disorders, it is important that the cardiovascular field be cognizant of potential beneficial or untoward effects of modulating B-cell activity on atherosclerosis.

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Background Lipid metabolism has been associated with the development of autism. The omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) readily undergo lipid peroxidation and conversion to malondialdehyde (MDA). MDA-modified low-density lipoprotein (MDA-LDL) is a marker of lipid peroxidation. However, the association between PUFAs and MDA-LDL in the pathophysiology of autism spectrum disorder (ASD) is unclear. Materials and methods We studied the association between PUFAs and MDA-LDL in 16 individuals with ASD (mean age: 11.5 ± 5.7 years) and seven age- and sex-matched healthy controls (mean age: 10.0 ± 4.1 years). The Aberrant Behavior Checklist (ABC) was used to assess behavioral symptoms. We overcame the small sample size by using the adaptive LASSO for enhancing the accuracy of prediction and interpretability. We also estimated the coefficient of variation for an appropriate variable selection and compared additional prior studies to support the findings. Thus, we conducted a careful selection of appropriate candidates to account for confounding variables. Results The ASD group had significantly higher plasma MDA levels, eicosapentaenoic acid levels, and a higher ratio of plasma docosahexaenoic acid (DHA)/arachidonic acid (ARA) levels than the control group. Plasma levels of the omega-6 PUFA fraction, dihomo-γ-linolenic acid, and superoxide dismutase levels were significantly lower in the ASD group than in the control group. Total ABC scores were significantly higher in the ASD group than in the control group. Multiple linear regression and adaptive LASSO indicated that plasma DHA levels and plasma DHA/ARA ratios were significantly associated with total ABC scores and plasma levels of MDA-LDL. Conclusion Increased plasma levels of DHA and DHA/ARA ratio might be related to organic pollution. These neurobiological bases may induce neuronal deficiency associated with autistic behavioral symptoms in individuals with ASD.

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Cardiovascular events can occur after deferred revascularization, and malondialdehyde-modified low-density lipoprotein (MDA-LDL) has been suggested to be an atherogenic marker. We investigated the relationship between serum MDA-LDL levels and clinical outcomes in patients with fractional flow reserve (FFR)-guided deferral of revascularization. Among 3084 patients undergoing coronary angiography, we retrospectively analyzed 127 patients with intermediate stenosis and deferred revascularization based on FFR > 0.80. Median follow-up interval was 30.4 months, and serum MDA-LDL was measured prior to the measurement of FFR. We evaluated the composite of major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, ischemia-driven deferred lesion revascularization, and any revascularization. MACEs occurred in 18 (14.2%) patients. The MACE group presented with significantly higher MDA-LDL levels than the non-MACE group (134.9 ± 33.3 U/L vs. 95.6 ± 32.2 U/L, P < 0.001). In analysis of the receiver operating characteristics curve for the prediction of MACEs, MDA-LDL presented a significantly larger area under the curve than low-density lipoprotein-cholesterol (LDL-C; 0.810 vs. 0.687, P = 0.042). Univariate Cox regression analysis indicated a significant relationship between MACEs and MDA-LDL (per 10 U/L, HR 1.20; P = 0.004), as did the multivariate model (per 10 U/L, HR 1.17; P = 0.019). When compared according to the median LDL-C (98 mg/dL), the MACE group had significantly higher MDA-LDL in both the high (147.2 ± 27.3 U/L vs. 113.9 ± 31.2 U/L, P = 0.001) and low (103.2 ± 27.3 U/L vs. 80.2 ± 24.0 U/L, P = 0.045) LDL-C groups. Serum MDA-LDL levels were associated with cardiac events in patients with deferral of revascularization based on FFR.

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BACKGROUND: Cardiac events can occur after drug-eluting stent (DES) implantation due to coronary plaque progression at non-stented sites. Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is suggested to be an atherogenic marker. This study investigated the relationship between serum MDA-LDL and angiographic progression after DES implantation.Methods and Results:In total, 207 patients who underwent percutaneous coronary intervention (PCI) using DES and follow-up coronary angiography were retrospectively analyzed. MDA-LDL was serially measured before PCI and at follow up. Persistent high MDA-LDL was defined as a MDA-LDL level more than the median value both before PCI and at follow up. Angiographic progression was assessed by serial analysis of quantitative coronary angiography. Angiographic progression occurred in 35 patients (16.9%). MDA-LDL before PCI was significantly higher in the progression group than the non-progression group in all patients (143.4±35.8 U/L vs. 103.0±33.5U/L, P<0.001) and in patients with controlled LDL-cholesterol (LDL-C <100 mg/dL both before PCI and at follow up; 121.8±32.7 U/L vs. 84.9±24.9 U/L, P<0.001). There were positive correlations between % diameter stenosis changes and serum MDA-LDL before PCI in all patients (r=0.33, P<0.01) and those with controlled LDL-C (r=0.23, P=0.04). In multivariate logistic regression analysis, persistent high MDA-LDL was an independent predictor of plaque progression. CONCLUSIONS: Increased serum MDA-LDL was associated with angiographic progression after DES implantation.

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Objective The triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio is related to insulin resistance (IR). However, information about whether or not the TG/HDL-C ratio is associated with low-density lipoprotein (LDL) subclasses in the Japanese population is limited. Methods In total, 1,068 Japanese subjects who underwent an annual health examination and who were not taking medications were recruited. The association between the TG/HDL-C ratio and LDL subclasses was investigated using correlation, multiple regression, and receiver operating characteristic analyses. Results A correlation analysis revealed that both malondialdehyde-modified low-density lipoprotein (MDA-LDL) and small dense low-density lipoprotein cholesterol (sdLDL-C) were positively associated with the TG/HDL-C ratio. Furthermore, a multiple linear regression analysis revealed that the TG/HDL-C ratio was positively associated with MDA-LDL and sdLDL-C in both men and women. The multiple logistic regression analysis also revealed that the TG/HDL-C ratio was positively associated with the upper tertile of MDA-LDL and sdLDL-C in men and women. The LDL-C levels increased with the increasing TG/HDL-C ratio. The MDA-LDL and sdLDL-C are known to be positively associated with LDL-C. However, within the same LDL-C range, both MDA-LDL and sdLDL-C levels increased with the TG/HDL-C ratio, except for MDA-LDL levels in the LDL-C <112 mg/dL group in women. These results further supported the notion that the TG/HDL-C ratio was positively associated with the MDA-LDL and sdLDL-C levels, especially in the higher LDL-C range, in both men and women. The optimal cut-off points of the TG/HDL-C ratio for the upper tertile of MDA-LDL and sdLDL-C were 1.85 and 2.03 in men and 0.88 and 1.30 in women, respectively. Conclusion The TG/HDL-C ratio is positively associated with MDA-LDL and sdLDL-C in Japanese subjects. The relationship was particularly notable in subjects with high LDL-C levels.

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The role of malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidized LDL, in the pathophysiology of autism spectrum disorder (ASD) is unclear. We studied association between MDA-LDL and behavioral symptoms in 11 individuals with ASD and 7 age -matched normal controls. Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). Because small sample size in this study, three measures were conducted: first, employment of adaptive Lasso for enhancing the accuracy of prediction and interpretability; second, calculation of coefficient of variation for an appropriate selection of plasma variables; and third, selection of good candidates of plasma variables. Plasma levels of MDA-LDL, eicosapentaenoic acid, docosahexaenoic acid (DHA) and DHA/arachidonic acid ratios were significantly higher, while plasma superoxide dismutase (SOD) levels were significantly lower in the ASD group than in the control group. The total ABC scores were significantly higher in the ASD group than in the control group. Multiple linear regression analysis and the adaptive Lasso revealed association of increased plasma DHA levels with the ABC total scores and increased plasma MDA-LDL levels. Such association between DHA and plasma MDA-LDL levels may contribute to behavior in individuals with ASD.

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Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) acts as a marker of oxidative stress and is associated with atherosclerotic cardiovascular disease. The relationship between serum MDA-LDL levels and aortic stiffness (AS) in patients with hemodialysis (HD) was evaluated. There were 155 HD patients enrolled in this study. Carotid-femoral pulse wave velocity (cfPWV) was measured by a validated tonometry system. Patients with cfPWV >10 m/s were used to define the AS group, while those with values of ≤10 m/s were regarded as the control group. Serum MDA-LDL levels were measured using a commercial enzyme-linked immunosorbent assay. Sixty-eight patients (43.9%) who were defined as AS sufferers, and were older, had a higher percentage of diabetes and hypertension and higher systolic blood pressure and serum MDA-LDL level compared to subjects in the control group. After adjusting for factors significantly associated with AS by multivariable logistic regression analysis, it was revealed that serum MDA-LDL levels, diabetes, and hypertension were independent predictors of AS in HD patients. Multivariable forward stepwise linear regression analysis also showed that a logarithmically transformed MDA-LDL level was significantly correlated with cfPWV values in HD patients. In HD patients, a high serum MDA-LDL level was positively associated with cfPWV values and was a significant predictor of the development of high AS.

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Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

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OBJECTIVE: To investigate the effect of minimally modified low-density lipoprotein (mmLDL) on ETA receptor of mesenteric artery (endothelin type A receptors, ETA) in mice for the first time and whether autophagy is involved in this process. METHODS: Mice were injected mmLDL in the tail vein and intraperitoneally with Class III PI3K autophagy pathway inhibitor 6-amino-3-methylpurine (3-MA) to explore the role of autophagy in mmLDL treated mice. The changes of vasoconstriction curve of mesenteric artery induced by ET-1 (endothelin 1) in mice were observed by a sensitive myograph system. ETA receptor was detected by RT-PCR quantitative mRNA and Western blot. The protein levels of Class III PI3K, Beclin-1, LC3-Ⅱ/, p62 and p-NF-κB, NF-κB were detected by Western blot. RESULTS: The contractility curve of ET-1 induced by mmLDL was significantly enhanced, showing that the Emax value increased from the nomal saline (NS) group (184.87±7.46)% to (319.91±20.31)% (P < 0.001), the pEC50 increased from NS group (8.05±0.05) to (9.11±0.09) (P<0.01). mmLDL up-regulated Class III PI3K,beclin-1,LC3-Ⅱ/ and down-regulated p62 protein level, at the same time, it also caused the ETA receptor mRNA level, protein expression increased significantly, up-regulated the protein level of p-NF-κB; intraperitoneal injection of 3-MA inhibits these effects of mmLDL. CONCLUSION: mmLDL can activate autophagy and down-stream NF-κB pathway through Class III PI3K/Beclin-1 pathway to up-regulate ETA receptor.

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Although ezetimibe has potential value as an add-on therapy to statins, it is not established whether the addition of ezetimibe to statin therapy is more effective than double-dose statin monotherapy. We conducted a crossover design study. Twenty-one coronary artery disease (CAD) patients whose lipid profiles had not achieved Japanese guideline recommendations (JAS 2017), despite receiving low-dose statin therapy, were divided into two groups. Group A received ezetimibe 10 mg in addition to the baseline dose of statin for the first 3 months and was then switched to monotherapy with a double dose of statin for the next 3 months. Group B first received a double dose of statin for 3 months and was then switched to ezetimibe 10 mg in addition to a baseline dose of statin for the next 3 months. Compared with the baseline, double-dose statin therapy reduced low-density lipoprotein (LDL)-cholesterol (from 118 ± 22 to 104 ± 15 mg/dL, P < 0.05) and malondialdehyde-modified LDL (MDA-LDL) (from 142 ± 35 to 126 ± 24 U/L, P < 0.05) but did not lower high-sensitivity C-reactive protein (hsCRP) (3.02 ± 0.47 and 2.98 ± 0.41 log [ng/ml]). The addition of ezetimibe to a baseline dose of statin further reduced LDL-cholesterol (to 89 ± 15, P < 0.0001) and MDA-LDL (to 114 ± 22 U/L, P < 0.001) and reduced hsCRP (to 2.78 ± 0.38 log (ng/ml), P < 0.05). The changes in the levels of MDA-LDL (R = 0.548, P = 0.010) and hsCRP (R = 0.473, P < 0.05) were significantly correlated with the change in the LDL-cholesterol level after the addition of ezetimibe. Add-on ezetimibe treatment appears superior to double-dose statin therapy in CAD patients with poorly controlled dyslipidemia in terms of reductions in LDL-cholesterol level, lipid peroxidation, and inflammation.

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Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs.

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OBJECTIVES: The current study aimed to explore whether minimally modified low-density lipoprotein (mmLDL) via tail vein injection upregulates the ETB and α1 receptors in mouse mesenteric arteries by activating the PI3K/Akt pathway. METHODS: The contraction curves of the mesenteric arteries caused by sarafotoxin 6c (S6c, ETB receptor agonist) and phenylephrine (PE, α1 receptor agonist) were measured by a myograph system. Serum oxLDL was detected using enzyme-linked immunosorbent assays. The levels of the ETB receptor, the α1 receptor, PI3K, p-PI3K and p-Akt were detected using real-time polymerase chain reaction and Western blot analyses. KEY FINDINGS: Minimally modified low-density lipoprotein noticeably enhanced the contraction effect curves of S6c and PE, with significantly increased Emax values (P < 0.01), compared to those of the control group. This treatment significantly increased the mRNA expression and protein levels of the ETB and α1 receptors and the protein levels of p-PI3K and p-Akt in the vessel wall (P < 0.01). LY294002 inhibited the effect of mmLDL. CONCLUSIONS: An increase in mmLDL activated the PI3K/Akt pathway, which upregulated the expression of the ETB and α1 receptors and enhanced the ETB and α1- receptor-mediated contractile function.

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