How safe are proprotein convertase subtilisinekexin type 9 inhibitors in diabetes?

PURPOSE OF REVIEW: To examine the safety of proprotein convertase subtilisinekexin type 9 (PCSK9) inhibitors in patients with diabetes, specifically focusing on their impact on glucose metabolism. RECENT FINDINGS: Patients with diabetes often require intensified lipid-lowering therapy. PCSK9 inhibitors can reduce low-density lipoprotein cholesterol (LDL-C) concentrations by approximately 60%, and significantly reduce cardiovascular risk when added to statin therapy. Some studies have suggested an association between low LDL-C levels and an increased risk of new-onset diabetes, and genetics has almost consistently shown an increased glucose concentration and risk of diabetes. Most clinical trials have not demonstrated a deterioration in glycaemic control in patients with diabetes after the use of PCSK9 inhibitors, and they do not lead to other significant treatment-emergent adverse events. SUMMARY: Although the majority of patients with diabetes are undergoing background statin therapy, which may mask potential adverse effects of PCSK9 inhibitors on glycaemic control, current data suggest that the benefits outweigh the risks for diabetic patients using PCSK9 inhibitors. Considering the different nature of genetic studies and of clinical trials, close monitoring of glucose parameters is necessary, especially in individuals with prediabetes.

Empagliflozin ameliorates vascular calcification in diabetic mice through inhibiting Bhlhe40-dependent NLRP3 inflammasome activation.

Type 2 diabetes mellitus (T2DM) patients exhibit greater susceptibility to vascular calcification (VC), which has a higher risk of death and disability. However, there is no specific drug for VC therapy. NLRP3 inflammasome activation as a hallmark event of medial calcification leads to arterial stiffness, causing vasoconstrictive dysfunction in T2DM. Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), restrains hyperglycemia with definite cardiovascular benefits. Given the anti-inflammatory activity of EMPA, herein we investigated whether EMPA protected against VC in the aorta of T2DM mice by inhibiting NLRP3 inflammasome activation. Since db/db mice receiving a normal diet developed VC at the age of about 20 weeks, we administered EMPA (5, 10, 20 mg·kg-1·d-1, i.g) to 8 week-old db/db mice for 12 weeks. We showed that EMPA intervention dose-dependently ameliorated the calcium deposition, accompanied by reduced expression of RUNX2 and BMP2 proteins in the aortas. We found that EMPA (10 mg·kg-1·d-1 for 6 weeks) also protected against VC in vitamin D3-overloaded mice, suggesting the protective effects independent of metabolism. We showed that EMPA (10 mg·kg-1·d-1) inhibited the abnormal activation of NLRP3 inflammasome in aortic smooth muscle layer of db/db mice. Knockout (KO) of NLRP3 significantly alleviated VC in STZ-induced diabetic mice. The protective effects of EMPA were verified in high glucose (HG)-treated mouse aortic smooth muscle cells (MOVASs). In HG-treated NLRP3 KO MOVASs, EMPA (1 µM) did not cause further improvement. Bioinformatics and Western blot analysis revealed that EMPA significantly increased the expression levels of basic helix-loop-helix family transcription factor e40 (Bhlhe40) in HG-treated MOVASs, which served as a negative transcription factor directly binding to the promotor of Nlrp3. We conclude that EMPA ameliorates VC by inhibiting Bhlhe40-dpendent NLRP3 inflammasome activation. These results might provide potential significance for EMPA in VC therapy of T2DM patients.

Association between glucose levels and all-cause mortality in cancer survivors: findings from NHANES 1999-2018.

BACKGROUND: Hyperglycemia is a rapidly increasing risk factor for cancer mortality worldwide. However, the dose‒response relationship between glucose levels and all-cause mortality in cancer survivors is still uncertain. METHODS: We enrolled 4,491 cancer survivors (weighted population 19,465,739) from the 1999-2019 National Health and Nutrition Examination Survey (NHANES). Cancer survivors were defined based on the question of whether they had ever been diagnosed with cancer by a doctor or a health professional. Hemoglobin A1c (HbA1c) was selected in this study as a stable marker of glucose level. Mortality was ascertained by linkage to National Death Index records until December 31, 2019. Cox proportional hazard, Kaplan‒Meier survival curves and Restricted cubic spline regression models were used to evaluate the associations between HbA1c and all-cause mortality risk in cancer survivors. RESULTS: In NHANES, after adjusting for confounders, HbA1c had an independent nonlinear association with increased all-cause mortality in cancer survivors (nonlinear P value < 0.05). The threshold value for HbA1c was 5.4%, and the HRs (95% CI) below and above the threshold value were 0.917 (0.856,0.983) and 1.026 (1.010,1.043), respectively. Similar associations were found between fasting glucose and all-cause mortality in cancer survivors, and the threshold value was 5.7 mmol/L. CONCLUSIONS: HbA1c was nonlinearly associated with all-cause mortality in cancer survivors, and the critical value of HbA1c in decreased mortality was 5.4%, suggesting optimal glucose management in cancer survivors may be a key to preventing premature death in cancer survivors.

Association of serum five heavy metals level with all-cause and cause-specific mortality: a large population-based cohort study.

The study aimed to explore the association between five heavy metals exposure (Cadmium, Lead, Mercury, Manganese, and Selenium) and mortality [all-cause, cardiovascular disease (CVD), and cancer-related]. We integrated the data into the National Health and Nutrition Examination Survey from 2011 to 2018 years. A total of 16,092 participants were recruited. The link between heavy metals exposure and mortality was analyzed by constructing a restricted cubic spline (RCS) curve, Cox proportional hazard regression model, and subgroup analysis. The RCS curve was used to show a positive linear relationship between Cadmium, Lead, and all-cause mortality. In contrast, there was a negative linear correlation between Mercury and all-cause mortality. Additionally, Manganese and Selenium also had a J-shaped and L-shaped link with all-cause mortality. The positive linear, positive linear, negative liner, J-shaped, and L-shaped relationships were observed for Cadmium, Lead, Mercury, Manganese, and Selenium and CVD mortality, respectively. Cadmium, Lead, Mercury, and Selenium were observed to exhibit positive linear, U-shaped, negative linear, and L-shaped relationships with cancer-related mortality, respectively. There was an increase and then a decrease in the link between Manganese and cancer-related morality. This study revealed the correlation between the content of different elements and different types of mortality in the U.S. general population.

Trends in lipid profiles and control of LDL-C among adults with diabetes in the United States: An analysis of NHANES 2007-2018.

BACKGROUND AND AIM: To determine trends in lipid profiles and lipid control in US adults with diabetes and assess variation in these trends across sex and race/ethnicity from 2007 to 2018. METHODS AND RESULTS: Serial cross-sectional analysis of data from diabetic adults participating in the National Health and Nutrition Examination Survey (NHANES; 2007-2008 to 2017-2018). Among the 6116 participants included (weighted mean age, 61.0 years; 50.7% men), age-adjusted TC (p for trend < 0.001), LDL-C (p for trend < 0.001), TG (p for trend = 0.006), TG/HDL-C (p for trend = 0.014) and VLDL-C (p for trend = 0.015) decreased significantly. Age-adjusted LDL-C levels were consistently higher in women than in men over the study period. Age-adjusted LDL-C improved significantly for diabetic whites and blacks but did not change significantly for the other races/ethnicity. Lipid parameters improved for non-coronary heart disease (CHD) diabetic adults, except for HDL-C, while no lipid parameter significantly changed for diabetic adults with concomitant CHD. Among diabetic adults receiving statin therapy, age-adjusted lipid control remained unchanged from 2007 to 2018, as did adults with concomitant CHD. However, age-adjusted lipid control improved significantly for men (p for trend < 0.01) and diabetic Mexican Americans (p for trend < 0.01). In 2015-2018, female diabetic participants receiving statins had lower odds of achieving lipid control (OR: 0.55; 95% CI: 0.35-0.84; P = 0.006) than men. Differences in lipid control across different races/ethnicities no longer existed. CONCLUSIONS: Lipid profiles improved in the US adults with diabetes from 2007 to 2018. Although rates of lipid control did not improve nationally in adults receiving statins, these patterns varied by sex and race/ethnicity.

Efficacy and safety of PCSK9 inhibitors in patients with diabetes: A systematic review and meta-analysis.

AIMS: Individuals with diabetes have increased cardiovascular risk. Although PCSK9 inhibitors bring about a wide reduction in lipids, there is uncertainty about the effects for diabetic patients. We conducted a systematic review and meta-analysis to assess the efficacy and safety of PCSK9 inhibitors for diabetes. DATA SYNTHESIS: We performed a meta-analysis comparing treatment with PCSK9 inhibitors versus controls up to July 2022. Primary efficacy endpoints were percentage changes in lipid profile parameters. We used random effects meta-analyses to combine data. Subgroups of diabetic patients (by diabetes type, baseline LDL-C, baseline HbA1c and follow-up time) were also compared. We included 12 RCTs comprising 14,702 patients. Mean reductions in LDL-C were 48.20% (95% CI: 35.23%, 61.17%) in patients with diabetes. Reductions observed with PCSK9 inhibitors were 45.23% (95% CI: 39.43%, 51.02%) for non-HDL-cholesterol, 30.39% (95% CI: 24.61%, 36.17%) for total cholesterol, 11.96% (95% CI: 6.73%, 17.19%) for triglycerides, 27.87% (95% CI: 22.500%, 33.17%) for lipoprotein(a), 42.43% (95% CI: 36.81%, 48.06%) for apolipoprotein B; increases in HDL-C of 5.97% (95% CI: 4.59%, 7.35%) were also observed. There was no significant difference in fasting plasma glucose (FPG) (WMD: 2.02 mg/mL; 95% CI: -1.83, 5.87) and HbA1c (WMD: 1.82%; 95% CI: -0.63, 4.27). Use of a PCSK9 inhibitor was not associated with increased risk of treatment-emergent adverse event (TEAE) (p = 0.542), serious adverse event (SAE) (p = 0.529) and discontinuations due to AEs (p = 0.897). CONCLUSIONS: PCSK9 inhibitor therapy should be considered for all diabetic individuals at high risk of atherosclerotic cardiovascular disease. REGISTRATION CODE IN PROSPERO: CRD42022339785.

Global, regional, and national time trends in cancer mortality attributable to high fasting plasma glucose: an age-period cohort analysis.

BACKGROUND: High fasting plasma glucose (HFPG) is the fastest-growing risk factor for cancer deaths worldwide. We reported the cancer mortality attributable to HFPG at global, regional, and national levels over the past three decades and associations with age, period, and birth cohort. METHODS: Data for this study were retrieved from the Global Burden of Disease Study 2019, and we used age-period-cohort modelling to estimate age, cohort and period effects, as well as net drift (overall annual percentage change) and local drift (annual percentage change in each age group). RESULTS: Over the past 30 years, the global age-standardized mortality rate (ASMR) attributable to HFPG has increased by 27.8%. The ASMR in 2019 was highest in the male population in high sociodemographic index (SDI) areas (8.70; 95% CI, 2.23-18.04). The net drift for mortality was highest in the female population in low SDI areas (2.33; 95% CI, 2.12-2.55). Unfavourable period and cohort effects were found across all SDI quintiles. Cancer subtypes such as "trachea, bronchus, and lung cancers", "colon and rectal cancers", "breast cancer" and "pancreatic cancer" exhibited similar trends. CONCLUSIONS: The cancer mortality attributable to HFPG has surged during the past three decades. Unfavourable age-period-cohort effects on mortality were observed across all SDI quintiles, and the cancer mortality attributable to HFPG is expected to continue to increase rapidly in the future, particularly in lower SDI locations. This is a grim global public health issue that requires immediate attention.

Association of Systemic Immune Inflammation Index with Estimated Pulse Wave Velocity, Atherogenic Index of Plasma, Triglyceride-Glucose Index, and Cardiovascular Disease: A Large Cross-Sectional Study.

In the U.S. general population, there is a lack of understanding regarding the association between the systemic immune inflammation (SII) index and estimated pulse wave velocity (ePWV), atherogenic index of plasma (AIP), and triglyceride-glucose (TyG) index and cardiovascular disease (CVD). As a result, the objective of our research was to investigate the association between the SII index and ePWV, AIP, and TyG index and incident CVD. We used the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018 to conduct this study. The correlation between the SII index and ePWV, AIP, and TyG index was examined using generalized additive models with smooth functions. In addition, the association between SII index and triglyceride (TC), high-density lipoprotein cholesterol (HDL-C), and fast glucose (FBG) also were explored. Finally, we further performed multivariable logistic regression analysis, restricted cubic spline (RCS) plots, and subgroup analysis to study the connection between the SII index and CVD. Our analysis included 17389 subjects from the NHANES database. A substantial positive association existed between SII, WV, and the TyG index. In addition, with the increase of the SII index, AIP showed a trend of decreasing first, then rising, and then decreasing. The SII index was inversely and linearly associated with triglyceride (TG), while positively and linearly associated with fast glucose (FBG). However, high-density lipoprotein cholesterol (HDL-C) had a tendency of first declining, then climbing, and finally falling with the rise in the SII index. After adjusting for potential confounders, compared with the lowest quartiles, the odds ratios with 95% confidence intervals for CVD across the quartiles were 0.914 (0.777, 1.074), 0.935 (0.779, 1.096), and 1.112 (0.956, 1.293) for SII index. The RCS plot showed an inverse U-shaped curve relationship between the SII index and CVD. Overall, this study found a strong correlation between a higher SII index and ePWV and the TyG index. Additionally, these cross-sectional data also revealed a U-shaped connection between the SII index and CVD.

Relationship between a novel non-insulin-based metabolic score for insulin resistance (METS-IR) and coronary artery calcification.

BACKGROUND AND AIMS: A novel non-insulin-based metabolic score for insulin resistance (METS-IR) index has been proposed as a simple and reliable alternative insulin resistance (IR) marker, but its the predictive value in asymptomatic adults with coronary artery calcification (CAC) remains unclear. METHODS AND RESULTS: We enrolled 1576 participants without cardiovascular disease (CVD), who underwent multidetector computed tomography. Logistic regression, restricted cubic spline models and receiver operating characteristic (ROC) curves were used to examine the association between METS-IR, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride glucose index (TyG index) and CAC. In multivariate logistic regression analysis, the increase in METS-IR was independently associated with a higher prevalence of CAC (all P < 0.05 in Models 1-3). Furthermore, restricted cubic splines indicated that the significance of METS-IR in predicting CAC was higher than that of other IR indexes. In ROC curve analysis, without considering the P value, the area under the curve of CAC predicted by METS-IR was higher than that of other IR indexes (METS-IR, 0.607; TyG index, 0.603; TG/HDL-C, 0.577). CONCLUSION: Compared with other IR indexes, METS-IR may have better discrimination ability in predicting the incidence of CAC in asymptomatic adults without CVD.

Association between hemoglobin glycation index and subclinical myocardial injury in the general population free from cardiovascular disease.

BACKGROUND AND AIMS: The relationship between hemoglobin glycation index (HGI) and the diagnosis and prognosis of cardiovascular disease (CVD) has been verified by previous studies. However, it remains unknown whether HGI has a predictive effect on subclinical myocardial injury (SC-MI). The purpose of the present study was to explore the relationship between HGI and SC-MI in the general population free from CVD. METHODS AND RESULTS: The present study included 6009 participants free of CVD from the third National Health and Nutrition Examination Survey. Binary Logistic regression analysis was used to tested the association between HGI and SC-MI. As results, the HGI was significantly higher in participants with SC-MI compared with those without, and the HGI was positively correlated with SC-MI and other metabolic disorder parameters. Each 1-unit increase of HGI and glycated hemoglobin A1c (HbA1c) was independently associated with higher risk of SC-MI (P < 0.05), while fasting plasma glucose (FPG) was no longer a predictive indicator of SC-MI with the increase of confounding factors [OR (95% CI): 1.001 (0.999-1.003), P = 0.305]. And in the subgroup analysis, HGI, only in participants without diabetes, was independently associated with higher risk of SC-MI, while HbA1c and FPG had no independent predictive role in both diabetic and non-diabetic participants. CONCLUSIONS: HGI was a significant predictor of SC-MI in the general population free from CVD.

Serum periostin as a predictor of early recurrence of atrial fibrillation after catheter ablation.

Catheter ablation is an effective method of rhythm therapy for atrial fibrillation (AF). AF recurrence is a common problem after catheter ablation. The aim of this study was to investigate influence factors of early recurrence after catheter ablation for AF. One hundred and three consecutive patients with AF were enrolled and underwent catheter ablation. Venous blood (Marked as A) was collected before ablation and left atrial blood (Marked as B) was collected after successful atrial septal puncture to detect serum periostin. After 3 months of follow-up, statistical analysis was made based on the recurrence of AF. 27 (26.2%) patients had a recurrence of atrial arrhythmia after catheter ablation. Patients with recurrent atrial arrhythmia had a larger left atrial volume (162.31 ± 47.76 vs. 141.98 ± 41.64,p = 0.039), and higher serum periostin levels (periostin A. 99.71 ± 16.475 vs. 90.36 ± 13.63, p = 0.005; periostin B. 103.95 ± 13.09 vs. 94.46 ± 15.85, p = 0.006) compared with the non-recurrent group. The numbers of patients with left atrial low-voltage areas (LVAs) were more in the recurrence group (p < 0.001). Left atrial volume, serum periostin and left atrial LVAs were included in univariate and multivariate COX regression analysis. It showed that left atrial LVAs (HR3.81; 95% CI 1.54 to 9.44; p = 0.004) and serum periostin A (HR1.07; 95% CI 1.02 to1.13; p = 0.008) were the independent predictors of AF recurrence. The cut-off value of serum periostin A was 87.95 ng/ ml (AUC, 0.681; sensitivity 88.9% and specificity 53.9%). Kaplan-Meier survival curve showed that the recurrence rate of AF was higher in patients with left atrial LVAs and higher serum periostin. The venous serum periostin level and left atrial LVAs were independent predictors of early recurrence of AF after catheter ablation.

Correlation analysis of coronary artery tortuosity and calcification score.

BACKGROUND: Coronary artery tortuosity (CAT) is regarded as a variation of vascular anatomy, and its relationship with coronary artery calcification (CAC) score is still not well clarified. Studying the correlation between coronary artery calcification scores and CAT to determine specific prevention and intervention populations seems to have more meaningful. METHODS: The study is a cross-sectional retrospective study, including 1280 patients. CAT is defined as the presence of at least three consecutive curvatures of more than 45°measured during systole or diastole of a major epicardial coronary artery. Multivariable regression analysis was used to adjust the clinical parameters directly affecting CAT. RESULTS: Of these individuals, 445 (35%) were evaluated having CAT, of which females are higher than males (59.1% vs. 40.9%). Moderate CAC score (101-400) (odds ratio (OR) 1.49, 95% confidence interval [95%CI] 1.05-2.10, P = 0.025) revealed significantly associated with CAT on univariable analysis. However, multivariable analysis after adjusting for confounding factors only indicated that CAT was positively correlated with female (OR 1.68, 95%CI 1.30-2.17, P < 0.001), hypertension (OR 1.35, 95% CI 1.04-1.75, P = 0.024), and age (OR 1.02, 95% CI 1.01-1.03, P = 0.001), while was negatively associated with body mass index (BMI) 24-27.9(OR 0.76, 95% CI 0.58-1.00, P = 0.044), and BMI > 28 (OR 0.46, 95% CI 0.31-0.68, P < 0.001). Further analysis stratified by gender showed that compared with non-CAT, CAT was significantly linked with moderate CAC score (OR 1.79, 95% CI 1.00-3.20, P = 0.048), hypertension (OR 1.54, 95% CI 1.07-2.22, P = 0.021), and high-density lipoprotein (HDL) (OR 1.86, 95% CI 1.07-3.24, P = 0.028), while was negatively related to BMI > 28 (OR 0.51, 95% CI 0.31-0.84, P = 0.008) in female patients. CONCLUSIONS: CAT is more likely to be found in females, connected with hypertension, age, and BMI. No significant correlation is found between the presence of tortuosity and calcium score or diameter stenosis on multivariable analysis. Whereas the CAT is associated with moderate CAC score in correlation analysis when women are selected as the main group.

Periostin promotes arterial calcification through PPARγ-related glucose metabolism reprogramming.

Extracellular matrix (ECM) exerts a series of biological functions and contributes to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the role of periostin in vascular calcification has yet to be fully investigated. As found in this study, recombinant periostin accelerated the thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS) ex vivo, which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition and suppressed PPARγ expression. Mechanistically, periostin caused overactivation of glycolysis and mitochondrial dysfunction in VSMCs as assessed by extracellular acidification rate, oxygen consumption rate, and mitochondrial respiratory chain complex activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients undergoing computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score in patients with coronary artery calcification (CAC). There was also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.NEW & NOTEWORTHY Periostin caused arterial calcification, overactivated glycolysis, and damaged OXPHOS. PPARγ agonists alleviated periostin-promoted arterial calcification and corrected abnormal glycolysis and unbalanced mitochondrial homeostasis. There exists a relationship between periostin and lactate in patients with CAC.

Mitochondria Homeostasis and Vascular Medial Calcification.

Vascular calcification occurs highly prevalent, which commonly predicts adverse cardiovascular events. The pathogenesis of calcification, a complicated and multifactorial process, is incompletely characterized. Accumulating evidence shows that mitochondrial dysfunction may ultimately be more detrimental in the vascular smooth muscle cells (VSMCs) calcification. This review summarizes the role of mitochondrial dysfunction and metabolic reprogramming in vascular calcification, and indicates that metabolic regulation may be a therapeutic target in vascular calcification.

Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy.

Arterial media calcification is related to mitochondrial dysfunction. Protective mitophagy delays the progression of vascular calcification. We previously reported that lactate accelerates osteoblastic phenotype transition of VSMC through BNIP3-mediated mitophagy suppression. In this study, we investigated the specific links between lactate, mitochondrial homeostasis, and vascular calcification. Ex vivo, alizarin S red and von Kossa staining in addition to measurement of calcium content, RUNX2, and BMP-2 protein levels revealed that lactate accelerated arterial media calcification. We demonstrated that lactate induced mitochondrial fission and apoptosis in aortas, whereas mitophagy was suppressed. In VSMCs, lactate increased NR4A1 expression, leading to activation of DNA-PKcs and p53. Lactate induced Drp1 migration to the mitochondria and enhanced mitochondrial fission through NR4A1. Western blot analysis of LC3-II and p62 and mRFP-GFP-LC3 adenovirus detection showed that NR4A1 knockdown was involved in enhanced autophagy flux. Furthermore, NR4A1 inhibited BNIP3-related mitophagy, which was confirmed by TOMM20 and BNIP3 protein levels, and LC3-II co-localization with TOMM20. The excessive fission and deficient mitophagy damaged mitochondrial structure and impaired respiratory function, determined by mPTP opening rate, mitochondrial membrane potential, mitochondrial morphology under TEM, ATP production, and OCR, which was reversed by NR4A1 silencing. Mechanistically, lactate enhanced fission but halted mitophagy via activation of the NR4A1/DNA-PKcs/p53 pathway, evoking apoptosis, finally accelerating osteoblastic phenotype transition of VSMC and calcium deposition. This study suggests that the NR4A1/DNA-PKcs/p53 pathway is involved in the mechanism by which lactate accelerates vascular calcification, partly through excessive Drp-mediated mitochondrial fission and BNIP3-related mitophagy deficiency.

HIF-1α/PDK4/autophagy pathway protects against advanced glycation end-products induced vascular smooth muscle cell calcification.

Osteogenic differentiation of VSMC is one of the main causes of diabetic vascular calcification, and AGEs accumulation accelerates the calcification of VSMCs in diabetic patients. Autophagy has also been found to play an important role in the process of vascular calcification. However, the potential link between AGEs, autophagy and vascular calcification is still unclear and was investigated in this study. Primary VSMCs were isolated from the thoracic aorta of Sprague Dawley rats and cultured with AGEs-BSA to induce osteogenic differentiation. VSMCs calcification was evaluated by measuring the calcium content, RUNX2 protein levels, and by Alizarin red S staining. We demonstrated that treatment of VSMCs with AGE-BSA increased the expression of HIF-1α and PDK4. AGE-BSA treatment increased LC3-II and decreased p62 protein levels. AGE-BSA exposure enhanced autophagic flux determined by mRFP-GFP-LC3 adenovirus, induced co-localization of LC3-II and LAMP-1, and increased the number of autophagasome under TEM. HIF-1α/PDK4 pathway was activated during AGEs-induced autophagy of VSMCs. In addition, autophagy played a protective role during AGE-induced calcification of VSMCs. In conclusion, AGEs enhance autophagy via the HIF-1α/PDK4 signaling pathway, and autophagy helps attenuate AGE-induced calcification of VSMCs.

Association of genetic polymorphisms in vascular endothelial growth factor with susceptibility to coronary artery disease: a meta-analysis.

BACKGROUND: Single nucleotide polymorphisms (SNPs) located in the vascular endothelial growth factor (VEGF) gene may be correlated with the susceptibility to coronary artery disease (CAD) - although results have been controversial. The aim of this meta-analysis is to clarify the effects of VEGF -2578A/C (rs699947), -1154G/A (rs1570360), +405C/G (rs2010963), and + 936C/T (rs3025039) polymorphisms on CAD risk. METHODS: Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the association between VEGF gene polymorphisms and CAD risk. Fixed- or random-effects model was used depending on the heterogeneity between studies. RESULTS: In total, 13 eligible articles containing 29 studies were analysed. The pooled analysis indicated that the VEGF gene polymorphisms of rs699947, rs2010963, and rs3025039 were associated with an increased risk of CAD, whereas no significant associations were observed with the rs1570360 polymorphism. A subgroup analysis stratified by ethnicity revealed that the rs699947 and rs3025039 polymorphisms were associated with CAD risk in Asian populations. In addition, stratification by control source indicated an increased risk of CAD susceptibility with the rs699947 polymorphism for population-based studies of reduced heterogeneity. CONCLUSIONS: In summary, we concluded that the VEGF gene polymorphisms rs699947, rs2010963, and rs3025039 are correlated with an elevated CAD risk.

Association between brain-derived neurotrophic factor and von Willebrand factor levels in patients with stable coronary artery disease.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in angiogenesis and maintenance of endothelial integrity. Whether circulating BDNF levels are associated with von Willebrand factor (vWF) levels, which are indicators of endothelial dysfunction is not known. This study investigated the association between plasma BNDF and vWF levels and whether these biomarkers could predict cardiovascular events at a 12-month follow-up in patients with stable coronary artery disease (CAD). METHODS: We recruited 234 patients with suspected angina pectoris. Subjects were divided into CAD (n = 143) and control (n = 91) groups based on coronary angiography. Plasma BDNF and vWF levels were measured using ELISA. Patients were followed-up for one year, and information on adverse cardiac events was collected. RESULTS: CAD patients exhibited significantly lower plasma BDNF and higher vWF levels than those of control patients. High vWF levels were associated with low BDNF levels even after adjustment for age, gender, low-density lipoprotein (LDL) levels, and the presence of diabetes mellitus. A receiver operating characteristic curve was used to determine whether low BDNF and high vWF levels could predict adverse cardiovascular events. The area under the curve for vWF and the inverse of BDNF were 0.774 and 0.804, respectively. CONCLUSIONS: These findings suggest that endothelial dysfunction is an important determinant of the impaired circulating BDNF levels, and they further reflected cardiovascular prognosis in stable CAD patients.

Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells.

BACKGROUND: Advanced glycation end-products (AGEs) are elevated under diabetic conditions and associated with insulin resistance, endothelial dysfunction and vascular inflammation in humans. It has been demonstrated that AGEs evoke oxidative and inflammatory reactions in endothelial cells through the interaction with a receptor for AGEs (RAGE). Here, we aimed to identify the cellular mechanisms by which AGEs exacerbate the endothelial dysfunction in human coronary artery endothelial cells (HCAECs). METHODS: 30 type 2 diabetic patients with or without coronary artery atherosclerosis were recruited for this study. Plasma levels of AGE peptides (AGE-p) were analyzed using flow injection assay. Endothelial function was tested by brachial artery flow-mediated vasodilatation (FMD). Further investigations were performed to determine the effects and mechanisms of AGEs on endothelial dysfunction in HCAECs. RESULTS: AGE-p was inversely associated with FMD in diabetic patients with coronary artery atherosclerosis in our study. After treated with AGEs, HCAECs showed significant reductions of eNOS mRNA and protein levels including eNOS and phospho-eNOS Ser1177, eNOS mRNA stability, eNOS enzyme activity, and cellular nitric oxide (NO) levels, whereas superoxide anion production was significantly increased. In addition, AGEs significantly decreased mitochondrial membrane potential, ATP content and catalase and superoxyde dismutase (SOD) activities, whereas it increased NADPH oxidase activity. Treatment of the cells with antioxidants SeMet, SOD mimetic MnTBAP and mitochondrial inhibitor thenoyltrifluoroacetone (TTFA) effectively blocked these effects induced by AGEs. AGEs also increased phosphorylation of the mitogen-activated protein kinases p38 and ERK1/2, whereas the specific inhibitors of p38, ERK1/2, and TTFA effectively blocked AGEs-induced reactive oxygen species production and eNOS downregulation. CONCLUSIONS: AGEs cause endothelial dysfunction by a mechanism associated with decreased eNOS expression and increased oxidative stress in HCAECs through activation of p38 and ERK1/2.

Anti-connective tissue growth factor detects and reduces plaque inflammation in early-stage carotid atherosclerotic lesions.

This study explored connective tissue growth factor (CTGF)-targeted ultrasmall superparamagnetic iron oxides (USPIOs) for noninvasive MRI of CTGF within carotid atherosclerotic lesions in apoE-deficient (apoE-/-) mice. Anti-CTGF polyclonal and nonspecific IgG antibodies were conjugated to polyethylene glycol-coated USPIOs, and apoE-/- carotid partial ligation-model mice were imaged via MRI before and after contrast administration. ApoE-/- mice were treated with CTGF-neutralizing antibodies for 3 weeks. Carotid artery diameter and plaque volume were measured via MRI in IgG and CTGF antibody-treated groups. Anti-CTGF-USPIO-treated macrophages showed the greatest iron uptake. MRI signal loss was observed in carotid atherosclerotic lesions 24 h after anti-CTGF-USPIO administration, consistent with the presence of nanoparticles, as indicated by pathological examinations. Atheromata in anti-CTGF-treated mice showed reduced macrophage deposition, CTGF expression, and plaque volume. Anti-CTGF-USPIOs can be used for the direct detection of CTGF and imaging of atherosclerotic lesions in vivo. CTGF is a potential therapeutic target for treating atherosclerosis.