Idebenone ameliorates statin-induced myotoxicity in atherosclerotic ApoE-/- mice by reducing oxidative stress and improving mitochondrial function.

Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE-/- mice and whether idebenone could counteract it. After administering simvastatin to ApoE-/- mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone's capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.

Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ.

BACKGROUND: Imeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic ß-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ). METHODS: ApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group. RESULTS: Imeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment. CONCLUSIONS: Imeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.

In vivo chronic exposure to inorganic mercury worsens hypercholesterolemia, oxidative stress and atherosclerosis in the LDL receptor knockout mice.

Heavy metal exposure leads to multiple system dysfunctions. The mechanisms are likely multifactorial and involve inflammation and oxidative stress. The aim of this study was to evaluate markers and risk factors for atherosclerosis in the LDL receptor knockout mouse model chronically exposed to inorganic mercury (Hg) in the drinking water. Results revealed that Hg exposed mice present increased plasma levels of cholesterol, without alterations in glucose. As a major source and target of oxidants, we evaluated mitochondrial function. We found that liver mitochondria from Hg treated mice show worse respiratory control, lower oxidative phosphorylation efficiency and increased H2O2 release. In addition, Hg induced mitochondrial membrane permeability transition. Erythrocytes from Hg treated mice showed a 50% reduction in their ability to take up oxygen, lower levels of reduced glutathione (GSH) and of antioxidant enzymes (SOD, catalase and GPx). The Hg treatment disturbed immune system cells counting and function. While lymphocytes were reduced, monocytes, eosinophils and neutrophils were increased. Peritoneal macrophages from Hg treated mice showed increased phagocytic activity. Hg exposed mice tissues present metal impregnation and parenchymal architecture alterations. In agreement, increased systemic markers of liver and kidney dysfunction were observed. Plasma, liver and kidney oxidative damage indicators (MDA and carbonyl) were increased while GSH and thiol groups were diminished by Hg exposure. Importantly, atherosclerotic lesion size in the aorta root of Hg exposed mice were larger than in controls. In conclusion, in vivo chronic exposure to Hg worsens the hypercholesterolemia, impairs mitochondrial bioenergetics and redox function, alters immune cells profile and function, causes several tissues oxidative damage and accelerates atherosclerosis development.

Impact of direct-acting antiviral on subclinical atherosclerosis in chronic hepatitis C infected patients.

INTRODUCTION: The impact of direct antiviral drugs (DAAs) on extrahepatic manifestations in chronic hepatitis C (CHC) has been poorly studied. AIM: To assess the prevalence of subclinical atherosclerosis in patients with CHC and the impact of DAAs on atherosclerotic lesions. Methods A 5-year prospective evaluative study, including patients followed for CHC at hepato-gastroenterology department. The subclinical atherosclerosis was assessed by ultrasound measurement of carotid intima-media thickness (IMTc) and the highest IMTc measurements from the left and right side defined the IMTc maximum (IMTc max). IMTc>75th percentile (IMTc75) define subclinical atherosclerosis with high cardiovascular risk. Patients were evaluated before (T0) and one year after DAAs therapy achievement (T1). RESULTS: At time T0, forty patients (median age: 55 y.; sex ratio M / F = 0.48), were included. Average value of IMTc max was 0.68 ± 0.16 mm. Subclinical atherosclerosis was noted in 82.5 %. At time T1, 28 patients were evaluated, all of whom completed sustained virological response (SVR). Compared to time T0, there was a significant increase in cholesterol (p = 0.001) and triglyceride (p = 0.009) levels. IMTc max was significantly higher at time T1 compared to T0 (0.75 Vs 0.67 mm, p = 0.04). Prevalence of IMTc75 was 82.1% at time T0 and 75% at time T1 (p=0.5). CONCLUSIONS: SVR, in CHC patients treated with DAA, was associated with worsening of carotid atherosclerotic lesions.

Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE-/- mice.

Nanoplastics (NPs) exposure is usually linked with abnormal inflammation and oxidative stress, which are high-risk triggers of atherosclerosis; however, whether this exposure causes the development of atherosclerosis is vague. Here, we found that PS NPs co-exposure with ox-LDL induces significant accumulation of lipid, as well as oxidative stress and inflammation in RAW264.7 macrophages. Using an ultrasound biomicroscope (UBM), we observed the emergence of atherosclerotic plaques at the aortic arch of apolipoprotein knockout (ApoE-/-) mice after being exposed to PS NPs for three months. Oil-red O and hematoxylin-eosin (H&E) staining at the mice's aortic root also observed the deposition of lipids with plaque formation. Moreover, the development of atherosclerotic disease is associated with disturbances in lipid metabolism and oxidative stress damage in the mice liver. In conclusion, this study provides additional evidence to further understand the possible cardiovascular damage caused by NPs exposure.

Accumulation of Iron Oxide-Based Contrast Agents in Rabbit Atherosclerotic Plaques in Relation to Plaque Age and Vulnerability Features.

Purpose: In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI). Methods: The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats. Results: Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg. Conclusion: Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.

Silymarin prevents endothelial dysfunction by upregulating Erk-5 in oxidized LDL exposed endothelial cells.

Extracellular signal-regulated kinase (Erk)-5 is a key mediator of endothelial cell homeostasis, and its inhibition causes loss of critical endothelial markers leading to endothelial dysfunction (ED). Circulating oxidized low-density lipoprotein (oxLDL) has been identified as an underlying cause of ED and atherosclerosis in metabolic disorders. Silymarin (Sym), a flavonolignan, possesses various pharmacological activities however its preventive mechanism in ED warrants further investigation. Here, we have examined the effects of Sym in regulating the expression of Erk-5 and ameliorating ED using in vitro and in vivo models. Primary human umbilical vein endothelial cells (pHUVECs) viability was measured by MTT assay; mRNA and protein expression by RT-qPCR and Western blotting; tube-formation assay was performed to examine endothelialness. In in-vivo experiments, normal chow-fed mice (control) or high-fat diet (HFD)-fed mice were administered Sym or Erk-5 inhibitor (BIX02189) and body weight, blood glucose, plasma-LDL, oxLDL levels, and expression of EC markers in the aorta were examined. Sym (5 µg/ml) maintained the viability and tube-formation ability of oxLDL exposed pHUVECs. Sym increased the expression of Erk-5, vWF, and eNOS and decreased ICAM-1 at transcription and translation levels in oxLDL-exposed pHUVECs. In HFD-fed mice, Sym reduced the body weight, blood glucose, LDL-cholesterol, and oxLDL levels, and increased the levels of vWF and eNOS along with Erk-5 and decreased the level of ICAM-1 in the aorta. These data suggest that Sym could be a potent anti-atherosclerotic agent that could elevate Erk-5 level in the ECs and prevent ED caused by oxidized LDL during HFD-induced obesity in mice.

Combined use of anticoagulant and antiplatelet on outcome after stroke in patients with nonvalvular atrial fibrillation and systemic atherosclerosis.

This study aimed to investigate whether there was a difference in one-year outcome after stroke between patients treated with antiplatelet and anticoagulation (OAC + antiplatelet) and those with anticoagulation only (OAC), when comorbid atherosclerotic disease was present with non-valvular atrial fibrillation (NVAF). This was a retrospective study using a prospective cohort of consecutive patients with ischemic stroke. Patients with NVAF and comorbid atherosclerotic disease were assigned to the OAC + antiplatelet or OAC group based on discharge medication. All-cause mortality, recurrent ischemic stroke, hemorrhagic stroke, myocardial infarction, and bleeding events within 1 year after the index stroke were compared. Of the 445 patients included in this study, 149 (33.5%) were treated with OAC + antiplatelet. There were no significant differences in all outcomes between groups. After inverse probability of treatment weighting, OAC + antiplatelet was associated with a lower risk of all-cause mortality (hazard ratio 0.48; 95% confidence interval 0.23-0.98; P = 0.045) and myocardial infarction (0% vs. 3.0%, P < 0.001). The risk of hemorrhagic stroke was not significantly different (P = 0.123). OAC + antiplatelet was associated with a decreased risk of all-cause mortality and myocardial infarction but an increased risk of ischemic stroke among patients with NVAF and systemic atherosclerotic diseases.

Effects of omega-3, omega-6, and total dietary polyunsaturated fatty acid supplementation in patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis.

Background: Uncertainty exists about the link between omega-3 fatty acid, omega-6 fatty acid, and total polyunsaturated fatty acid (PUFA) intake and mortality in atherosclerotic cardiovascular disease (ASCVD) patients, and no meta-analyses summarize the relationship between these various types of PUFAs and ASCVD. Methods: Web of Science, PubMed, EBSCO and Cochrane Library up to November 30, 2022 were searched for prospective randomized controlled studies investigating the relationships among omega-3, omega-6, and PUFA intake and mortality and cardiovascular events in ASCVD patients. This study has been registered at PROSPERO (No. CRD42023407566). Results: This meta-analysis included 21 publications from 17 studies involving 40 861 participants published between 1965 and 2022. In ASCVD patients, omega-3 may lower all-cause mortality (RR: 0.90, 95% CI [0.83, 0.98], I2 = 8%), CVD mortality (RR: 0.82, 95% CI [0.73, 0.91], I2 = 34%) and CVD events (RR: 0.90, 95% CI [0.86, 0.93], I2 = 79%). Subgroup analyses showed that EPA or EPA ethyl ester supplementation reduced CVD events, while the mixture of EPA and DHA had no significant impact. Long-chain omega-3 consumption of 1.0-4.0 g per d reduced death risk by 3.5% for each 1 g per d increase. Omega-6 and PUFA had no significant effect on mortality or CVD events, with low-quality evidence and significant heterogeneity. Conclusions: omega-3 intake is associated with a reduced risk of all-cause mortality, CVD mortality, and CVD events in ASCVD patients, while omega-6 or total PUFA intake showed no significant association. Increasing the omega-3 intake by 1 g per d resulted in a 3.5% decrease in the risk of death. These findings support the recommendation of supplements with omega-3 fatty acids for the secondary prevention of ASCVD.

Exploring the adverse effects of 1,3,6,8-tetrabromo-9H-carbazole in atherosclerotic model mice by metabolomic profiling integrated with mechanism studies in vitro.

Given its wide distribution in the environment and latent toxic effects, 1,3,6,8-tetrabromo-9H-carbazole (1368-BCZ) is an emerging concern that has gained increasing attention globally. 1368-BCZ exposure is reported to have potential cardiovascular toxicity. Although atherosclerosis is a cardiovascular disease and remains a primary cause of mortality worldwide, no evidence has been found regarding the impact of 1368-BCZ on atherosclerosis. Therefore, we aimed to explore the deleterious effects of 1368-BCZ on atherosclerosis and the underlying mechanisms. Serum samples from 1368-BCZ-treated atherosclerotic model mice were subjected to metabolomic profiling to investigate the adverse influence of the pollutant. Subsequently, the molecular mechanism associated with the metabolic pathway of atherosclerotic mice that was identified following 1368-BCZ exposure was validated in vitro. Serum metabolomics analysis revealed that 1368-BCZ significantly altered the tricarboxylic acid cycle, causing a disturbance in energy metabolism. In vitro, we further validated general markers of energy metabolism based on metabolome data: 1368-BCZ dampened adenosine triphosphate (ATP) synthesis and increased reactive oxygen species (ROS) production. Furthermore, blocking the aryl hydrocarbon receptor (AhR) reversed the high production of ROS induced by 1368-BCZ. It is concluded that 1368-BCZ decreased the ATP synthesis by disturbing the energy metabolism, thereby stimulating the AhR-mediated ROS production and presumably causing aggravated atherosclerosis. This is the first comprehensive study on the cardiovascular toxicity and mechanism of 1368-BCZ based on rodent models of atherosclerosis and integrated with in vitro models.

Low-level exposure to lead and atherosclerosis in the carotid arteries: Results from the Swedish population-based cohort SCAPIS.

BACKGROUND: Lead exposure is associated with cardiovascular disease. Atherosclerosis has been hypothesized to be one of the underlying mechanisms behind this association. AIM: To investigate whether lead exposure is associated with an increased risk of atherosclerosis in the carotid arteries in a large Swedish population-based cohort. METHODS: We performed a cross-sectional study using data from the population-based Swedish CardioPulmonary bioImage Study (SCAPIS), including 5622 middle-aged men and women, enrolled 2013-2018. Blood lead (B-Pb), measured by inductively coupled plasma mass spectrometry, was used as exposure biomarker. The presence of atherosclerotic plaque in the carotid arteries (yes/no), total plaque area (mm2) and the presence of large plaques (>25 mm2) were determined by ultrasonography. Associations between B-Pb and the different outcomes were analysed using Poisson and linear regression models, adjusted for potential confounders. RESULTS: Atherosclerotic plaque was present in 57% of the individuals, for whom the median total plaque area was 16 mm2 (range: 0.2-222). The median B-Pb concentration was 14 µg/L (range: 0.75-203). After adjusting for potential confounders, individuals in the fourth quartile of B-Pb (Q4) had a prevalence ratio (PR) for plaque of 1.08 (95% CI: 1.01, 1.16) when compared with the first quartile (Q1). A 10 µg/L increase in B-Pb concentrations was associated with an increase of 0.92 mm2 (95% CI: 0.14, 1.71) in total plaque area. The PR for large plaque was 1.09 (95% CI: 0.84, 1.42 for Q4 vs Q1). CONCLUSIONS: This study shows an association between B-Pb and atherosclerosis in the carotid arteries providing some support for the hypothesis that atherosclerosis is one of the mechanisms underlying the association between lead exposure and cardiovascular disease.

Dual action of macrophage miR-204 confines cyclosporine A-induced atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA-204 (miR-204) transcription. We therefore hypothesised that miR-204 is involved in the development of CsA-induced atherosclerosis. EXPERIMENTAL APPROACH: ApoE-/- mice with macrophage-miR-204 overexpression were generated to determine the effects of miR-204 on CsA-induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR-204 effects. KEY RESULTS: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high-fat diet-induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE-/- mice, respectively. miR-204 levels decreased in circulating monocytes and plaque lesions during CsA-induced atherosclerosis. The upregulation of miR-204 in macrophages inhibited CsA-induced atherosclerotic plaque formation but did not affect serum lipid levels. miR-204 limited the CsA-induced foam cell formation by reducing the expression of the scavenger receptors SR-BII and CD36. SR-BII was post-transcriptionally regulated by mature miR-204-5p via 3'-UTR targeting. Additionally, nuclear-localised miR-204-3p prevented the CsA-induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR-BII or CD36 expression restoration dampened the beneficial effects of miR-204 on CsA-induced atherosclerosis. CONCLUSION AND IMPLICATIONS: Macrophage miR-204 ameliorates CsA-induced atherosclerosis, suggesting that miR-204 may be a potential target for the prevention and treatment of CsA-related atherosclerotic side effects.

Impairment of Autophagy Mediates the Uric-Acid-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells.

INTRODUCTION: Hyperuricemia may be involved in the phenotypic transformation of vascular smooth muscle cells, thus promoting the occurrence of atherosclerosis, and autophagy may be one of the important links, but little is known about the specific molecular mechanism. METHODS: We established a mouse model of hyperuricemia and studied the relationship between changes in autophagy levels and the phenotypic transformation of muscle cells. RESULTS: Our study found that high uric acid levels promote the phenotypic transformation of muscle cells by inhibiting autophagy, thus enhancing their proliferation and migration abilities. If autophagy is restored, phenotypic transformation can be reversed by reducing the levels of the transcription factor Kruppel-like factor 4. CONCLUSION: Uric acid may induce the phenotypic transformation of muscle cells and promote the occurrence of atherosclerosis by disrupting normal autophagy.

Deletion of vascular thromboxane A2 receptors and its impact on angiotensin II-induced hypertension and atherosclerotic lesion formation in the aorta of Ldlr-deficient mice.

The thromboxane A2 receptor (TP) has been shown to play a role in angiotensin II (Ang II)-mediated hypertension and pathological vascular remodeling. To assess the impact of vascular TP on Ang II-induced hypertension, atherogenesis, and pathological aortic alterations, i.e. aneurysms, we analysed Western-type diet-fed and Ang II-infused TPVSMC KO/Ldlr KO, TPEC KO/Ldlr KO mice and their respective wild-type littermates (TPWT/Ldlr KO). These analyses showed that neither EC- nor VSMC-specific deletion of the TP significantly affected basal or Ang II-induced blood pressure or aortic atherosclerotic lesion area. In contrast, VSMC-specific TP deletion abolished and EC-specific TP deletion surprisingly reduced the ex vivo reactivity of aortic rings to the TP agonist U-46619, whereas VSMC-specific TP knockout also diminished the ex vivo response of aortic rings to Ang II. Furthermore, despite similar systemic blood pressure, there was a trend towards less atherogenesis in the aortic arch and a trend towards fewer pathological aortic alterations in Ang II-treated female TPVSMC KO/Ldlr KO mice. Survival was impaired in male mice after Ang II infusion and tended to be higher in TPVSMC KO/Ldlr KO mice than in TPWT/Ldlr KO littermates. Thus, our data may suggest a deleterious role of the TP expressed in VSMC in the pathogenesis of Ang II-induced aortic atherosclerosis in female mice, and a surprising role of the endothelial TP in TP-mediated aortic contraction. However, future studies are needed to substantiate and further elucidate the role of the vascular TP in the pathogenesis of Ang II-induced hypertension, aortic atherosclerosis and aneurysm formation.

Association between long-term exposure to ambient air pollution and lesion ischemia in patients with atherosclerosis.

BACKGROUND AND AIMS: Air pollution has been associated with coronary artery disease. The underlying mechanisms were understudied, especially in relation to coronary stenosis leading to myocardial ischemia. Advances in computed tomography (CT) allow for novel quantification of lesion ischemia. We aim to investigate associations between air pollution exposures and fractional flow reserve on CT (CT-FFR), a measure of coronary artery blood flow. METHODS: CT-FFR, which defines a ratio of maximal myocardial blood flow compared to its normal value (range: 0-100%), was characterized in 2017 patients with atherosclerosis between 2015 and 2017. Exposures to ozone (O3), nitrogen dioxide (NO2), and fine particulate matter (PM2.5) were estimated using high-resolution exposure models. Linear and logistic regression models were used to assess the association of each air pollutant with CT-FFR and with the prevalence of clinically relevant myocardial ischemia (CT-FFR <75%). RESULTS: Participants were on average 60.1 years old. Annual mean O3, NO2, PM2.5 were 61, 47 and 60 µg/m3, respectively. Mean CT-FFR value was 76.9%. In the main analysis, a higher level of O3 was associated with a lower CT-FFR value (-1.74%, 95% CI: -2.85, -0.63 per 8 µg/m3) and a higher prevalence of myocardial ischemia (odds ratio: 1.32, 95% CI: 1.05-1.65), adjusting for potential confounders such as risk factors and plaque phenotypes, independent of the effects of exposure to NO2 and PM2.5. No associations were observed for PM2.5 or NO2 with CT-FFR. CONCLUSIONS: Long-term exposure to O3 is associated with lower CT-FFR value in atherosclerotic patients, indicating higher risk of lesion ischemia.

Cigarette smoking and air pollution exposure and their effects on cardiovascular diseases.

Cardiovascular disease (CVD) has no socioeconomic, topographical, or sex limitations as reported by the World Health Organization (WHO). The significant drivers of CVD are cardio-metabolic, behavioral, environmental, and social risk factors. However, some significant risk factors for CVD (e.g., a pitiable diet, tobacco smoking, and a lack of physical activities), have also been linked to an elevated risk of cardiovascular disease. Lifestyles and environmental factors are known key variables in cardiovascular disease. The familiarity with smoke goes along with the contact with the environment: air pollution is considered a source of toxins that contribute to the CVD burden. The incidence of myocardial infarction increases in males and females and may lead to fatal coronary artery disease, as confirmed by epidemiological studies. Lipid modification, inflammation, and vasomotor dysfunction are integral components of atherosclerosis development and advancement. These aspects are essential for the identification of atherosclerosis in clinical investigations. This article aims to show the findings on the influence of CVD on the health of individuals and human populations, as well as possible pathology and their involvement in smoking-related cardiovascular diseases. This review also explains lifestyle and environmental factors that are known to contribute to CVD, with indications suggesting an affiliation between cigarette smoking, air pollution, and CVD.

Relationships of Liver X Receptor Antagonists and Atherosclerosis in Drinking Water from Six Chinese Major Cities.

While environmental factors have been considered contributors to atherosclerosis, it remains unclear whether drinking water promotes foam cell formation, the initial event of atherosclerosis. This study revealed that drinking water from six major cities in China, namely, Harbin, Jinan, Shanghai, Wuhan, Chongqing, and Zhuhai, significantly promoted foam cell formation in an in vitro macrophage model at a minimum concentration fold of 2. Moreover, cholesterol efflux was significantly impeded by all samples at 2-16-fold, while cholesterol influx was induced only by samples from Jinan and Chongqing at 16-fold, suggesting the dominant role of efflux in foam cell formation. Interestingly, except for the sample from Jinan, the samples exhibited complete inhibition of liver X receptor α (LXRα) activities at 160-fold, indicating the potential role of chemicals in drinking water in promoting foam cell formation by antagonizing LXRα. Through LXRα protein affinity selection-mass spectrometry, we identified ten LXRα-binding compounds, with efavirenz being revealed for the first time as a significant inducer of foam cell formation through LXRα antagonism. Overall, this study clarifies the atherosclerotic risks posed by drinking water and demonstrates the efavirenz-related atherosclerotic effects.

Effect of moderate-intensity statin with ezetimibe combination vs. high-intensity statin therapy according to sex in patients with atherosclerosis.

We aimed to evaluate sex differences in the effects of moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg plus ezetimibe) versus high-intensity statin (rosuvastatin 20 mg) monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). This was a sex-specific subgroup analysis of the RACING trial that evaluated the interaction between sex and treatment strategies for the primary outcome (composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years). Of 3780 patients in the RACING trial, 954 (25.2%) were women. Regardless of sex, the effect of moderate-intensity statin with ezetimibe combination therapy on primary outcome compared with high-intensity statin monotherapy was similar (hazard ratio [HR] 0.98 [0.63-1.52] in women; HR 0.90 [0.71-1.14] in men). The rate of discontinuation or dose reduction of study drugs due to intolerance was lower in the ezetimibe combination group than in the high-intensity statin monotherapy group in both women (4.5% vs. 8.6%, P = 0.014) and men (4.8% vs. 8.0%, P < 0.001). LDL cholesterol levels of < 70 mg/dL at 1, 2, and 3 years were more frequently achieved in the ezetimibe combination group than in the high-intensity statin monotherapy group (all P < 0.001) in both sexes. There were no significant interactions between sex and treatment groups regarding the primary outcome, discontinuation, or dose reduction of study drugs, or the proportion of achievement of LDL cholesterol levels < 70 mg/dL. The effect of ezetimibe combination therapy for the 3-year composite outcomes was not different in both men and women. The benefits of ezetimibe combination therapy on LDL cholesterol lowering and drug tolerance were similarly observed regardless of sex.Trial registration: https://clinicaltrials.gov ; Unique identifier: NCT03044665.

Confounding Effects of Tamoxifen: Cautionary and Practical Considerations for the Use of Tamoxifen-Inducible Mouse Models in Atherosclerosis Research-Brief Report.

BACKGROUND: In recent years, fate-mapping lineage studies in mouse models have led to major advances in vascular biology by allowing investigators to track specific cell populations in vivo. One of the most frequently used lineage tracing approaches involves tamoxifen-inducible CreERT-LoxP systems. However, tamoxifen treatment can also promote effects independent of Cre recombinase activation, many of which have not been fully explored. METHODS: To elucidate off-target effects of tamoxifen, male and female mice were either unmanipulated or injected with tamoxifen or corn oil. All mice received PCSK9 (proprotein convertase subtilisin/kexin type 9)-AAV (adeno-associated virus) injections and a modified Western diet to induce hypercholesterolemia. After 2 weeks, serum cholesterol and liver morphology were assessed. To determine the duration of any tamoxifen effects in long-term atherosclerosis experiments, mice received either 12 days of tamoxifen at baseline or 12 days plus 2 sets of 5-day tamoxifen boosters; all mice received PCSK9-AAV injections and a modified Western diet to induce hypercholesterolemia. After 24 weeks, serum cholesterol and aortic sinus plaque burden were measured. RESULTS: After 2 weeks of atherogenic treatment, mice injected with tamoxifen demonstrated significantly reduced serum cholesterol levels compared with uninjected- or corn oil-treated mice. However, there were no differences in PCSK9-mediated knockdown of LDL (low-density lipoprotein) receptors between the groups. Additionally, tamoxifen-treated mice exhibited significantly increased hepatic lipid accumulation compared with the other groups. Finally, the effects of tamoxifen remained for at least 8 weeks after completion of injections, with mice demonstrating persistent decreased serum cholesterol and impaired atherosclerotic plaque formation. CONCLUSIONS: In this study, we establish that tamoxifen administration results in decreased serum cholesterol, decreased plaque formation, and increased hepatic lipid accumulation. These alterations represent significant confounding variables in atherosclerosis research, and we urge future investigators to take these findings into consideration when planning and executing their own atherosclerosis experiments.

The mediation effect of lipids, blood pressure and BMI between air pollutant mixture and atherosclerotic cardiovascular disease: The CHCN-BTH cohort study.

BACKGROUND: The combine effect of air pollutant mixture on atherosclerotic cardiovascular disease (ASCVD) remain undefined. This study aims to explore the association between long-term exposure of air pollutants and ASCVD, focusing on the mediating role of lipids, blood pressure and BMI. METHODS: This study was based on the CHCN-BTH cohort study. The annual concentrations of air pollutants and PM2.5 constituents were sourced from in the Tracking Air Pollution in China (TAP) and ChinaHighAirPollutants (CHAP) datasets from 2014 to 2019. A Cox mixed-effects model was used to investigate the associations between long-term exposure of air pollutants and ASCVD. The combined impact of the air pollutant mixture was assessed using Quantile g-Computation. Stratified, sensitivity, and mediation analyses were conducted. RESULTS: A total of 27,134 participants aged 18-80 were recruited in the present study. We found that each IQR increase of PM2.5, PM1, NO2, O3, BC, SO42-, and OM were significantly associated with the incidence of ASCVD, the hazard ratios (HRs) and 95 % confidence interval (CI) were 1.55 (1.35, 1.78), 1.46 (1.27, 1.67), 1.30 (1.21, 1.39), 1.66 (1.41,1.95), 2.14 (1.63, 2.83), 1.65 (1.25, 2.17) and 1.92(1.52, 2.45), respectively. The combined effect of air pollutant mixture on ASCVD was 1.79 (1.46, 2.20), PM2.5 contributed 83.3 % to this combined effect. Mediation effect models suggested that air pollutants and ASCVD might be mediated through SBP, DBP, HDL-C, LDL-C, hsCRP and BMI (mediation proportion range from 1.3 % to 26.1 %), Notably, HDL-C played mediation roles of 11.3 % (7.0 %, 18.4), 26.1 % (17.7 %, 38.1 %) and 25.4 % (15.4, 47.7 %) in the effects of long-term exposure to PM2.5, PM1 and OM on ASCVD, respectively. CONCLUSIONS: Long-term, high-level air pollutant exposure was significantly associated with an elevated risk of ASCVD, particularly for PM2.5. Blood pressure, lipids and BMI, especially HDL-C, may mediate the effects of air pollutants exposure on ASCVD.