Progression Of Early Atherosclerosis Research Articles

A potential early-atheroprotective target: Irgm1 mediates lymphangiogenesis through LEC autophagy by Tfeb translocation

Lymphatic dysfunction is a pivotal pathological mechanism underlying the development of early atherosclerotic plaques. Potential targets of lymphatic function must be identified to realize the early prevention and treatment of atherosclerosis (AS). The immunity-related GTPase Irgm1 is involved in orchestrating cellular autophagy and apoptosis. However, the effect of Irgm1 on early AS progression, particularly through alterations in lymphatic function, remains unclear. In this study, we confirmed the protective effect of lymphangiogenesis on early-AS in vivo. Subsequently, an in vivo model of early AS mice with Irgm1 knockdown shows that Irgm1 reduces early atherosclerotic plaque burden by promoting lymphangiogenesis. Given that lymphatic endothelial cell (LEC) autophagy significantly contributes to lymphangiogenesis, Irgm1 may enhance lymphatic circulation by promoting LEC autophagy. Moreover, Irgm1 orchestrates autophagy in LECs by inhibiting mTOR and facilitating nuclear translocation of Tfeb. Collectively, these processes lead to lymphangiogenesis. Thus, this study establishes a link between Irgm1 and early AS, thus revealing a novel mechanism by which Irgm1 exerts an early protective influence on AS within the context of lymphatic circulation. The insights gained from this study have the potential to revolutionize the approach and management of AS onset.

Modeling Foam Cell Formation in A Hydrogel-Based 3D-Intimal Model: A Study of The Role of Multi-Diseases During Early Atherosclerosis.

Monocyte recruitment and transmigration are crucial in atherosclerotic plaque development. The multi-disease complexities aggravate the situation and continue to be a constant concern for understanding atherosclerosis plaque development. Herein, a 3D hydrogel-based model that integrates disease-induced microenvironments is sought to be designed, allowing us to explore the early stages of atherosclerosis, specifically examining monocyte fate in multi-disease complexities. As a proof-of-concept study, murine cells are employed to develop the model. The model is constructed with collagen embedded with murine aortic smooth muscle cells and a murine endothelial monolayer lining. The model achieves in vitro disease complexities using external stimuli such as glucose and lipopolysaccharide (LPS). Hyperglycemia exhibits a significant increase in monocyte adhesion but no enhancement in monocyte transmigration and foam cell conversion compared to euglycemia. Chronic infection achieved by LPS stimulation results in a remarkable augment in initial monocyte attachment and a significant increment in monocyte transmigration and foam cells in all concentrations. Moreover, the model exhibits synergistic sensitivity under multi-disease conditions such as hyperglycemia and infection, enhancing initial monocyte attachment, cell transmigration, and foam cell formation. Additionally, western blot data prove the enhanced levels of inflammatory biomarkers, indicating the model's capability to mimic disease-induced complexities during early atherosclerosis progression.

IPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia.

Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.

The Level of Intima-Media Thickness in Patients with Metabolic Syndrome in Poland Depending on the Prevalence of Type 2 Diabetes

Background: Metabolic syndrome (MetS), increasingly diagnosed among the Polish population, is a combination of factors that are associated with an increased risk of atherosclerosis and cardiovascular diseases. Intima-media thickness (IMT) of the common carotid artery has been suggested as, simply, a non-invasive and reproducible marker of the early stages of the atherosclerotic process. The carotid IMT can also be a strong predictor of future cerebral and cardiovascular events. The aim of our study was to evaluate atherosclerotic lesions in carotid vessels in patients with MetS depending on the presence of DMt2 and to assess which demographic factors affect the level of IMT. The study involved 335 subjects diagnosed with MetS, including 211 females (65%) and 124 males (37%) aged 37–82. The diagnosis of MetS was made on the basis of the International Diabetes Federation (IDF) criteria. The patients were divided into two subgroups: with DMt2 and without DMt2. The value of IMT depended on gender, education, and smoking status. We noticed that patients with DMt2 had the highest measurement of IMT compared with other groups (1.01 vs. 0.98). Additionally, a statistically significant difference between the subgroup with DMt2 and those without DMt2 was found (1.01 vs. 0.92; p < 0.005). Ultrasound assessment of the carotid IMT should be used more often in the diagnosis and monitoring of high cardiovascular risk and early progression of atherosclerosis, especially in patients with MetS with current DMt2.

Monitoring the Progression of Early Atherosclerosis Using a Fluorescence Nanoprobe for the Detection and Imaging of Phosphorylation and Glucose Levels

AbstractMonitoring the early stage of atherosclerosis (AS) without plaque formation is of great significance. Herein, we developed a metal organic framework (MOF)‐based fluorescence nanoprobe to analyze the progression of AS by assessing the levels of protein phosphorylation and glucose in blood and tissue. The probe was prepared by post‐modification of the MOF with iodine (I3−)‐rhodamine B (RhB) associate, which realizes the specific recognition of target object through the metal joint ZrIV and I3−‐RhB, respectively. We investigated different stages of target object changes in the early non‐plaque stage of AS in blood. It was found that the levels of phosphate and glucose in the blood were higher than those of the normal mice. The results of two‐photon images showed that early AS mice had higher levels of protein phosphorylation and glucose than that of the normal mice. The present study provides a suitable fluorescence tool for further revealing the pathogenesis and progression of AS.

Monitoring the Progression of Early Atherosclerosis Using a Fluorescence Nanoprobe for the Detection and Imaging of Phosphorylation and Glucose Levels.

Monitoring the early stage of atherosclerosis (AS) without plaque formation is of great significance. Herein, we developed a metal organic framework (MOF)-based fluorescence nanoprobe to analyze the progression of AS by assessing the levels of protein phosphorylation and glucose in blood and tissue. The probe was prepared by post-modification of the MOF with iodine (I3 - )-rhodamine B (RhB) associate, which realizes the specific recognition of target object through the metal joint ZrIV and I3 - -RhB, respectively. We investigated different stages of target object changes in the early non-plaque stage of AS in blood. It was found that the levels of phosphate and glucose in the blood were higher than those of the normal mice. The results of two-photon images showed that early AS mice had higher levels of protein phosphorylation and glucose than that of the normal mice. The present study provides a suitable fluorescence tool for further revealing the pathogenesis and progression of AS.

Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells

Vascular Smooth Muscle Cells (VSMCs) are known to be the key drivers of intimal thickening which contribute to early progression of atherosclerosis. VSMCs are the major producers of extracellular matrix within the vessel wall and in response to atherogenic stimuli they could modify the type of matrix proteins produced. Serotonin receptor 2B (5-HT2B receptor/HTR2B) has been implicated in several chronic fibrotic and vascular diseases. Although studies have successfully demonstrated the efficacy of HTR2B blockade in attenuating fibrotic disease, the role of 5-HT2B receptor in TGFβ mediated VSMC differentiation remain largely unknown. In the present study, we investigated the potential of targeting the 5-HT2B receptor to prevent TGFβ induced VSMCs differentiation. Our results showed that 5-HT2B receptors are expressed in human atherosclerotic lesion and HTR2B expression positively correlated to the VSMCs markers. We show that AM1125, a selective 5-HT2B receptor inhibitor, significantly inhibits TGFβ1 induced production of collagen and CTGF. The investigation of underlying mechanisms indicated that 5-HT2B receptor antagonism blocks phospho-Smad2 mediated downstream signaling of TGFβ1 in vascular smooth muscle cells. Collectively, the HTR2B/TGF-β1/Phospho-Smad2 pathway plays a critical role in the regulation of VSMCs differentiation. Our findings might serve 5-HT2B receptor as a therapeutic target to limit TGF-β1 induced VSMC differentiation.

Apolipoproteins as potential communicators play an essential role in the pathogenesis and treatment of early atherosclerosis.

Atherosclerosis as the leading cause of the cardiovascular disease is closely related to cholesterol deposition within subendothelial areas of the arteries. Significantly, early atherosclerosis intervention is the critical phase for its reversal. As atherosclerosis progresses, early foam cells formation may evolve into fibrous plaques and atheromatous plaque, ulteriorly rupture of atheromatous plaque increases risks of myocardial infarction and ischemic stroke, resulting in high morbidity and mortality worldwide. Notably, amphiphilic apolipoproteins (Apos) can concomitantly combine with lipids to form soluble lipoproteins that have been demonstrated to associate with atherosclerosis. Apos act as crucial communicators of lipoproteins, which not only can mediate lipids metabolism, but also can involve in pro-atherogenic and anti-atherogenic processes of atherosclerosis via affecting subendothelial retention and aggregation of low-density lipoprotein (LDL), oxidative modification of LDL, foam cells formation and reverse cholesterol transport (RCT) in macrophage cells. Correspondingly, Apos can be used as endogenous and/or exogenous targeting agents to effectively attenuate the development of atherosclerosis. The article reviews the classification, structure, and relationship between Apos and lipids, how Apos serve as communicators of lipoproteins to participate in the pathogenesis progression of early atherosclerosis, as well as how Apos as the meaningful targeting mass is used in early atherosclerosis treatment.

Hormonal characteristics of androgen status and their relationship with the anthropometric and metabolic parameter in men depending on the severity of hypertension

Background. According to the literature data, long-term and poorly controlled hypertension (HTN) leads to target organs damage, and in some cases, to the development of associated diseases, the severity of which in men may be partly due to the characteristics of the androgenic status.The aim: to reveal the features of hormonal indicators of androgen status and their relationship with the anthropometric and metabolic characteristics of the therapeutic clinic male patients, depending on the severity of HTN.Materials and methods. 296 men aged 59,0 [54,0; 65,0] years with confirmed HTN were examined. All study participants in the morning on an empty stomach underwent anthropometry, determination of metabolic and androgenic status, and assessment of comorbid burden. Depending on the severity of hypertension, all patients were divided into two groups (G): G1 (n = 134) – patients with hypertension without a history of coronary artery disease or stroke; G2 (n = 162) – patients with hypertension with a history of ischemic heart disease (IHD) and/or stroke.Results. In male patients of G2 with severe HTN, a decrease in the levels of free testosterone (FT) and, to a greater extent, dehydroepiandrosterone sulfate (DHEA-S), as well as total cholesterol, high and low density lipoproteins, was revealed. The correlation analysis performed revealed statistically significant negative correlations between the levels of total testosterone (TT) and FT with body mass index, the value of the ratio of waist circumference to hips, only the level of FT – with the presence of IHD, chronic heart failure (CHF), disorders of carbohydrate metabolism and abdominal type of fat distribution, and the level of DHEA-S – with the presence of IHD and CHF.Conclusion. A decrease in FT and DHEA-S is associated with early progression of atherosclerosis and the risk of developing HTN-associated cardiovascular events, which can aggravate the course of HTN.

Isobavachalcone attenuates TNF-α-induced ICAM-1 and VCAM-1 expression in human umbilical vein endothelial cells by regulating the NF-κB signaling pathway

Vascular inflammation activated by pro-inflammatory cytokines is an inflammatory response that occurs in the early stages of atherosclerosis. Endothelial dysfunction in vascular inflammation begins with the expression of cell surface adhesion molecules by pro-inflammatory cytokines. The purpose of this study was to evaluate and verify the vascular inflammatory effects of isobavachalcone. In this study, we investigated the effects of isobavachalcone on inflammatory responses in vascular inflammation induced by the tumor necrosis factor-α (TNF-α) in human umbilical vein endothelial cells (HUVECs). TNF-α stimulation significantly increased the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) proteins, and concentration-dependently decreased by isobavachalcone in HUVECs. Isobavachalcone suppressed TNF-α-induced ICAM-1 and VCAM-1 expression in HUVECs, thereby inhibiting TNF-α-induced increase in monocyte adhesion. In addition, isobavachalcone decreased the phosphorylation of the NF-κB (necrosis factor κB) p65 subunit. The findings of this study demonstrate that isobavachalcone prevents TNF-α-induced vascular inflammation and has the potential to protect against the early progression of atherosclerosis.

Downregulation of NAGLU in VEC Increases Abnormal Accumulation of Lysosomes and Represents a Predictive Biomarker in Early Atherosclerosis.

Cardiovascular diseases (CVDs), predominantly caused by atherosclerosis (AS), are the leading cause of mortality worldwide. Although a great number of previous studies have attempted to reveal the molecular mechanism of AS, the underlying mechanism has not been fully elucidated. The aberrant expression profiling of vascular endothelial cells (VECs) gene in early atherosclerosis (EAS) was analyzed according to the dataset (GSE132651) downloaded from the Gene Expression Omnibus (GEO) database. We primarily performed functional annotation analysis on the downregulated genes (DRGs). We further identified that α-N-acetylglucosaminidase (NAGLU), one of the DRGs, played a critical role in the progression of EAS. NAGLU is a key enzyme for the degradation of heparan sulfate (HS), and its deficiency could cause lysosomal accumulation and lead to dysfunctions of VECs. We found that siRNA knockdown of NAGLU in human umbilical vein endothelial cell (HUVEC) aggravated the abnormal accumulation of lysosomes and HS. In addition, the expression of NAGLU was reduced in the EAS model constructed by ApoE −/- mice. Furthermore, we also showed that heparin-binding EGF-like growth factor (HB-EGF) protein was upregulated while NAGLU knockdown in HUVEC could specifically bind to vascular endothelial growth factor receptor 2 (VEGFR2) and promote its phosphorylation, ultimately activating the phosphorylation levels of extracellular signal-regulated kinases (ERKs). However, the application of selective VEGFR2 and ERKs inhibitors, SU5614 and PD98059, respectively, could reverse the abnormal lysosomal storage caused by NAGLU knockdown. These results indicated that downregulation of NAGLU in HUVEC increases the abnormal accumulation of lysosomes and may be a potential biomarker for the diagnosis of EAS.

Abstract 12227: Atherosclerotic Risk Factors Associated With Carotid Plaque Progression Are Different Depending on the Severity of Plaque Stage: A Longitudinal Study in General Population

Background: Carotid plaque is a well-known prognostic factor for cardiovascular disease and stroke. However, it is unclear which atherosclerotic risk factors are related to plaque transformation in the non-pharmacological population. Purpose: To examine the atherosclerotic risk factors associated with the progression of carotid plaque according to the severity of atherosclerosis Methods: We investigated 738 male participants without medication who underwent the 1 st and the 2 nd health checkups (mean duration: 2.0±1.6 years). We measured carotid plaque thickness (PT) evaluated by using ultrasonography at three points of the right and left carotid artery. Plaque score (PS) was calculated by summing all the PT. We divided into three groups following previous reports: normal stage, PS<1.1 mm; early stage, 1.1 mm < PS<5.1 mm; advanced stage, PS > 5.1 mm. We used the risk factors such as age, body mass index, systolic blood pressure (SBP), fasting blood sugar, low-density lipoprotein cholesterol (LDL-C), smoking habits, and exercise habits for analysis. Results: At 1 st health checkup, 108 participants had already progressed to the advanced stage of carotid plaque, 454 participants had the early stage, and 176 participants had the normal stage. 14% of participants with the early stage at 1 st health checkup had progressed to the advanced stage at 2 nd health checkup, and 42% of participants with the normal stage at 1 st health checkup had progressed the early stage at 2 nd health checkup. In multivariate logistic regression analysis, SBP was an independent risk factor for progression of PS stage from the normal stage at 1 st health checkup to the early stage at 2 nd health checkup (SBP; OR 1.27, CI 1.01-1.60, p<0.05). In addition, LDL-C was an independent risk factor associated with further progression of carotid plaque from the early stage at 1 st health checkup to the advanced stage at 2 nd health checkup (LDL-C; OR 1.10, CI 1.00-1.21, p<0.05). Conclusions: SBP was associated with the carotid plaque progression of early atherosclerosis, while LDL-C was associated with the progression of advanced atherosclerosis. We should be aware of risk factors according to the stage of plaque progression.

Cannabis Seed Oil Alleviates Experimental Atherosclerosis by Ameliorating Vascular Inflammation in Apolipoprotein-E-Deficient Mice.

In recent decades, epidemiological, clinical, and experimental studies have demonstrated that a diet with antioxidant or anti-inflammatory function plays a central role in the prevention of atherosclerosis (AS). The purpose of this study was to explore the effects of Cannabis seed oil (CO) administration on in vitro antioxidant capacity as well as blood lipid profiles, lipid peroxidation, inflammatory response, and endothelial cell integrity. Female ApoE-/- mice were fed a high-cholesterol diet and administrated with CO or phosphate-buffered saline (PBS) and seal oil by gavage for 8 weeks. The results show that CO administration reduced the levels of serum triglycerides and low-density lipoprotein cholesterol at week 6. Additionally, a decrease in serum tumor necrosis factor α and nitric oxide was also observed. Moreover, results from CD31 staining and scanning electron microscopy revealed that CO treatment alleviated the endothelial cell damage and lipid deposition induced by a high-cholesterol diet. The ratio of lesion area to the total aorta area was 19.57% for the CO group, which was lower than the PBS control group (24.67%). Collectively, CO exerted anti-atherosclerotic effects by modulating serum lipid profiles and inflammatory responses and improving endothelial cell integrity and arterial lipid deposition. The results provide a promising preventive strategy for the early progression of AS.

Evaluation of the relationship between hepatic and cardiac iron overload with MRI T2* and carotid intima media thickness with Doppler ultrasound in beta thalassemia major patients

Background: Iron overload is caused early progression of atherosclerosis in beta thalassemia patients due to regular repeated blood transfusion. MRI T2* is a gold standard non-invasive method for detecting hepatic and cardiac iron overload. The aim of this study was the comparison of carotid intima media thickness (CIMT) in the patients and healthy control groups with Doppler ultrasound for early diagnosis of atherogenesis. Another purpose was to assess the relationship between CIMT and iron overload among patients. Materials and methods: This cross-sectional study was performed on twenty patients referred to the Sarvar clinic and twenty age- and sex-matched control group. The CIMT was measured with Color Doppler ultrasound in both groups. Then, MRI T2* results, demographic, and therapeutic information were extracted from their documents. Results: CIMT was insignificantly higher in the patients compared to the control group. For example, it was 0.49 ± 0.05 vs. 0.45 ± 0.03 (p = 0.009) for the right common carotid artery (RCCA) and 0.48 ± 0.06 vs. 0.46 ± 0.04 (p = 0.17) for the left common carotid artery (LCCA). There was no strong relationship between CIMT and age (p = 0.09 for RCCA, p = 0.00 for LCCA), sex, chelation type (for example, p = 0.51 for RCCA with Desferal and p = 0.91 for LCCA with Desferal), age at diagnosis, age at the beginning on transfusion (p = 0.49 for RCCA, p = 0.20 for LCCA), age at the start of chelator (p = 0.74 for RCCA, p = 0.78 for LCCA), and hepatic and cardiac iron overload. Conclusion: Preventive and curative methods should be planned to cease its progression. Furthermore, early initiation of chelator drugs with better efficacy and compliance may reverse the hepatotoxic and adverse myocardial effects of excessive iron.

Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis.

Cardiovascular disease remains the most frequent cause of death worldwide. Atherosclerosis, an underlying cause of cardiovascular disease, is an inflammatory disorder associated with endothelial dysfunction. The endothelin system plays a crucial role in the pathogenesis of endothelial dysfunction and is involved in the development of atherosclerosis. We aimed to reveal the expression levels of the endothelin-A receptor (ETAR) in the course of atherogenesis to reveal possible time frames for targeted imaging and interventions. We used the ApoE−/− mice model and human specimens and evaluated ETAR expression by quantitative rtPCR (qPCR), histology and fluorescence molecular imaging. We found a significant upregulation of ETAR after 22 weeks of high-fat diet in the aortae of ApoE−/− mice. With regard to translation to human disease, we applied the fluorescent probe to fresh explants of human carotid and femoral artery specimens. The findings were correlated with qPCR and histology. While ETAR is upregulated during the progression of early atherosclerosis in the ApoE−/− mouse model, we found that ETAR expression is substantially reduced in advanced human atherosclerotic plaques. Moreover, those expression changes were clearly depicted by fluorescence imaging using our in-house designed ETAR-Cy 5.5 probe confirming its specificity and potential use in future studies.

ENOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization.

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system and prevents the early progression of atherosclerosis; however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. Apolipoprotein E gene-deficient mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness and collagen content while decreasing the population of CD68-positive cells. Enhanced plaque stability by LEO was associated with the nitric oxide synthase (NOS)-nitric oxide (NO) system. LEO restored the balance between endothelial NOS(E)- and inducible NOS(iNOS)-derived NO production; suppressed the NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque, including cytokine interleukin 6; and downregulated the expression of adhesion molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with oxidized low-density lipoprotein-challenged human umbilical vein endothelial cells revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO system and mitigated inflammation contribute to the plaque-stabilizing effect of LEO. SIGNIFICANCE STATEMENT: LEO restored the balance between endothelial NOS and inducible NOS in NO production and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in apolipoprotein E gene-deficient mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness, and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial.

Novel findings to the biosynthetic pathway of magnoflorine and taspine through transcriptomic and metabolomic analysis of Croton draco (Euphorbiaceae)

BackgroundCroton draco is an arboreal species and its latex as well as some other parts of the plant, are traditionally used in the treatment of a wide range of ailments and diseases. Alkaloids, such as magnoflorine, prevent early atherosclerosis progression while taspine, an abundant constituent of latex, has been described as a wound-healer and antitumor-agent. Despite the great interest for these and other secondary metabolites, no omics resources existed for the species and the biosynthetic pathways of these alkaloids remain largely unknown.ResultsTo gain insights into the pathways involved in magnoflorine and taspine biosynthesis by C. draco and identify the key enzymes in these processes, we performed an integrated analysis of the transcriptome and metabolome in the major organs (roots, stem, leaves, inflorescences, and flowers) of this species. Transcript profiles were generated through high-throughput RNA-sequencing analysis while targeted and high resolution untargeted metabolomic profiling was also performed. The biosynthesis of these compounds appears to occur in the plant organs examined, but intermediaries may be translocated from the cells in which they are produced to other cells in which they accumulate.ConclusionsOur results provide a framework to better understand magnoflorine and taspine biosynthesis in C. draco. In addition, we demonstrate the potential of multi-omics approaches to identify candidate genes involved in the biosynthetic pathways of interest.

Lower Serum Indirect Bilirubin Levels are Inversely Related to Carotid Intima-Media Thickness Progression.

Bilirubin has been recognized as a potential endogenous inhibitor of atherosclerosis, being inversely associated with carotid intima-media thickness (CIMT). However, little information is available concerning the correlation between serum indirect bilirubin (IBIL), especially long-term IBIL level, and early atherosclerosis progression. This study was designed to evaluate the relationship between serum IBIL level and CIMT progression. A total of 2205 participants were enrolled in this Asymptomatic Polyvascular Abnormalities Community study (APAC study). CIMT was measured at baseline and 2-year follow-up. The participants were divided into four groups based on their serum IBIL levels at baseline. Both baseline and average serum IBIL values during the 2-year follow up were used in the analysis. Multivariable logistic regression and linear regression were used to assess the associations between serum IBIL and CIMT progression. The results showed that 51.93% (1145/2205) of participants were diagnosed with CIMT progression during the 2-year follow-up. Baseline serum IBIL level was significantly associated with the incidence of CIMT progression after adjusting for other potential confounding factors. Compared with the first quartile, adjusted odds ratios (OR) of the second, third, and fourth quartiles of IBIL were 0.70 [95% confidence interval (CI), 0.55-0.90], 0.68 (95% CI, 0.52-0.87), and 0.63 (95% CI, 0.49-0.82) (P = 0.0006), respectively. Serum IBIL level during the follow-up was also associated with CIMT progression in the univariate analysis (P = 0.0022), although no longer significant after adjusting for potential confounders in the multiple linear regression. The study demonstrated the inverse relationship between serum IBIL and CIMT progression. Lower serum IBIL level is an independent predictor of subclinical atherosclerosis.

The Inverse Relationship between Cardiorespiratory Fitness and Intima-Media Thickness with Prehypertensive Middle-Aged Women.

Individuals with prehypertension have a greater risk of developing hypertension and cardiovascular disease than those with normal blood pressure. Good cardiorespiratory fitness has been associated with a reduced risk for cardiovascular diseases, but whether it is related to slower progression of early atherosclerosis is unclear. We evaluated 442 women, aged 40-60 years, with resting systolic blood pressure 120-139 mmHg and diastolic blood pressure 80-89 mmHg, defined as prehypertension in cross-sectional study. Blood glucose, blood lipids and carotid intima-media thickness (CIMT) were measured at rest. Cardiorespiratory fitness (VO2peak) was measured by respiratory gas exchange during a treadmill exercise test. Participants were divided into three cardiorespiratory fitness levels: low, moderate, and high. The prevalence of subclinical carotid atherosclerosis was defined as a mean carotid intima-media thickness greater than the 75th percentile. After adjustment for various confounders, a high cardiorespiratory fitness level was associated with significantly lower SBP, DBP and CIMT compared with low and moderate fitness (p < 0.05). After adjustment for established risk factors, high and moderate fitness were each associated with significantly lower odds ratios for carotid atherosclerosis 0.74 (95% CI 0.45-0.92) and 0.70 (95% CI 0.46-0.95), respectively, compared with low fitness. Our results indicate that good cardiorespiratory fitness is associated with a slower progression of early atherosclerosis in middle-aged women. These findings are important, because they emphasize that middle-aged women can be evaluated for cardiorespiratory fitness to estimate their future risk for atherosclerotic vascular diseases.

2014 Jeffrey M. Hoeg Award Lecture: Transcriptional Control of Monocyte Development.

Monocytes and macrophages are key immune cells involved in the early progression of atherosclerosis. Transcription factors that control their development in the bone marrow are important therapeutic targets to control the numbers and functions of these cells in disease. This review highlights what is currently known about the transcription factors that are critical for monocyte development.