Lipoprotein Oxidation Research Articles

Mycoplasma pneumoniae drives macrophage lipid uptake via GlpD-mediated oxidation, facilitating foam cell formation.

Cardiovascular diseases, primarily caused by atherosclerosis, are a major public health concern worldwide. Atherosclerosis is characterized by chronic inflammation and lipid accumulation in the arterial wall, leading to plaque formation. In this process, macrophages play a crucial role by ingesting lipids and transforming into foam cells, which contribute to plaque instability and cardiovascular events. Recent studies have suggested that various pathogens are involved in the development of atherosclerosis, with Mycoplasma pneumoniae considered one of the potential candidates. Therefore, this study investigated whether this bacterium induces lipid accumulation in macrophages, which play a crucial role in the development of atherosclerosis, using the Raw264.7 model. Our findings revealed that M. pneumoniae infection promotes lipid droplet formation in macrophages. Glycerol 3-phosphate oxidase, GlpD, in the bacterium is involved in this process by producing reactive oxygen species, which in turn causes the oxidation of low-density lipoprotein. Furthermore, the significant increase in the expression of oxidized lipid receptors involved in the uptake of this oxidized lipid indicates that the bacteria promote lipid uptake in infected macrophages. These results suggest that M. pneumoniae has a direct pro-atherogenic effect, promoting the formation of atherosclerotic lesions through foam cell formation. Understanding the mechanisms by which M. pneumoniae influences atherosclerosis provides valuable insights for devising new therapeutic strategies for the prevention and management of cardiovascular diseases.

Combining In Vitro, In Vivo, and In Silico Approaches to Explore the Effect of Ceratonia siliqua and Ocimum basilicum Rich Phenolic Formula on Lipid Metabolism and Plasma Lipoprotein Oxidation in Mice Fed a High-Fat Diet: A Follow-Up Study.

Hyperlipidemia is a serious risk factor for cardiovascular diseases and liver steatosis. In this work, we explored the effect of an herbal formula (CBF) containing immature Ceratonia siliqua pods and Ocimum basilicum extracts on lipid metabolism disorders and lipoprotein-rich plasma (LRP) oxidation in mice. The phenolic composition was determined using HPLC-DAD analysis. The antioxidant activity was studied using various in vitro methods. Acute toxicity was evaluated in mice. Importantly, the effect of the CBF on lipid metabolism disorders was investigated in a high-fat diet (HFD) hyperlipidemia mouse model. An in silico study was carried out to predict underlying mechanisms. The HPLC analysis revealed gallic acid, cinnamic acid, and naringenin as major phenolics of the carob pod aqueous extract. Concerning the basil hydro-ethanolic extract, rosmarinic, chicoric, caftaric, and caffeic acids were the main phenolics. Accordingly, the CBF prevented LRP oxidation in a concentration-dependent manner. This formula is not toxic in mice (LD50 > 2000 mg/kg body weight). Moreover, animals administered the CBF at 200 mg/kg/day presented a significant decline in their body weight gain, adipose tissue weight, plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C) level, and glycaemia after 10 weeks' treatment. Accordingly, the CBF decreased the plasma atherogenic index and the LDL-C to HDL-C ratio and reduced the level of fats accumulated in the liver. The molecular docking study revealed that chicoric, rosmarinic, and caftaric acids, and naringenin bound particularly strongly to many proteins involved in the regulation of lipid and cholesterol metabolism. This includes the HMG-CoA reductase, PPARα/γ, PCSK9, Cyp7a1, and ATP-citrate lyase. The CBF could be a good source of natural supplements, functional foods, and pharmaceuticals effective in managing hyperlipidemia and oxidative stress and preventing their related cardiovascular disorders.

Oxidized low-density lipoproteins and their contribution to atherosclerosis

Lipoprotein oxidation is a critical early stage in the development of atherosclerosis, a disease characterized by the formation of plaque in arterial walls. It has been well-established that the oxidation of low-density lipoprotein (LDL) is a key factor in the progression of atherosclerosis. Oxidized LDL (Ox-LDL) possesses a range of atherogenic properties, contributing to endothelial dysfunction, foam cell formation, and inflammation within the arterial wall. The interaction between Ox-LDL and specific receptors on endothelial cells plays a crucial role in these processes. In this article, we will discuss the oxidation of LDL and the pro-atherogenic role of Ox-LDL, we will delve into the different types of LDL receptors involved in the uptake and metabolism of LDL, with a focus on their role in atherosclerosis. We will explore the mechanisms by which native LDL (nLDL) and Ox-LDL interact with these receptors, leading to the development and progression of atherosclerotic plaques. Then we will go through more in-depth discussion to explore the intricate role of scavenger receptors in the uptake of oxidized low-density lipoproteins (Ox-LDL) and their significant contribution to the pathogenesis of atherosclerosis. Understanding the intricacies of these receptor-ligand interactions is essential for developing targeted therapeutic strategies to combat atherosclerosis and its associated complications.

Coffee: Fuel for Your Day or Foe for Your Arteries.

Atherosclerosis, a major cause of cardiovascular diseases, is influenced by modifiable factors such as adiposity and blood cholesterol. Diet is crucial in these areas, particularly regarding antioxidant, inflammatory, and obesity effects. Coffee, a globally popular stimulant beverage, has garnered significant attention for its potential impact on cardiovascular diseases. Recent insights reinforce the need to re-examine the relationship between coffee consumption and atherosclerosis progression. Coffee's complex composition includes polyphenols, renowned for their antioxidant and anti-inflammatory properties as well as potential weight-reducing effects. In addition, studies have demonstrated that certain coffee compounds such as chlorogenic acid, caffeic, p-coumaric, and ferulic acid can prevent atherogenesis by preventing the oxidation of low-density lipoproteins. Conversely, diterpenes, found in some coffee brews, can elevate cholesterol levels, posing a risk to coronary health. Notably, coffee intake has been shown to influence gut microbiota diversity, potentially contributing to anti-obesity effects. This review explores the insights from preclinical and clinical studies investigating the potential mechanisms through which coffee consumption may reduce the risk of atherosclerosis-highlighting the potential benefits of moderate filtered coffee consumption and the potential risks associated with excessive coffee consumption. Understanding this relationship is crucial for informing public health recommendations and guiding future research.

Relationship Between Serum Levels of Oxidized Lipoproteins, Circulating Levels of Myeloperoxidase and Paraoxonase 1, and Diet in Young Subjects with Insulin Resistance.

Oxidized low-density lipoproteins (ox-LDLs) are involved in atherosclerotic plaque formation and progression and have been linked to insulin resistance (IR). Myeloperoxidase is a potent oxidant of lipoproteins related to atherogenic risk. High-density lipoproteins (HDLs) are considered antioxidants due to their association with paraoxonase 1 (PON1). However, HDL can also be oxidized (ox-HDL), and its relationship with IR has not been described. This study evaluated the relationship between circulating levels of myeloperoxidase and paraoxonase 1, diet, and serum levels of ox-LDL and ox-HDL in young people with IR. This cross-sectional study examined 136 young subjects (67 and 69 with and without insulin resistance, respectively). Serum levels of ox-LDL, ox-HDL, myeloperoxidase, and PON1 were quantified using an enzyme-linked immunosorbent assay. The nutritional dietary content of the foods was determined with a food frequency questionnaire, which was analyzed with Nutrimind 2013 software. Serum ox-HDL levels were higher in young subjects without IR than those with IR (p = 0.031). Women with IR presented increased ox-LDL levels compared with women without IR (p = 0.012) and men with IR (p < 0.001). In the IR group, serum ox-LDL levels were negatively correlated with total cholesterol, triglycerides, and LDL-C, whereas the correlation was positive in the insulin-sensitive group. Consumption of vitamins B1 and B2 was related to increased HDL-C levels, while higher ox-LDL levels were related to vitamin K intake. In addition, low energy consumption and phosphorus increased PON1 levels. The results suggest that insulin resistance in young women may promote lipoprotein oxidation, and the intake of B complex vitamins may have an antiatherogenic effect.

Endothelial Dysfunction with Aging: Does Sex Matter?

Oxidative stress and inflammation accompany endothelial dysfunction that results from the excessive or uncontrolled production of reactive oxygen and nitrogen species (RONS) in older adults. This study was designed to assess the usefulness of serum oxi-inflammatory component combinations in vascular disease prediction and prevention with regard to sex. Women (n = 145) and men (n = 50) aged 72.2 ± 7.8 years participated in this project. The females demonstrated the elevated production of hydrogen peroxide (H2O2) and nitric oxide (NO) responsible for intravascular low-density lipoprotein oxidation. NO generation was enhanced in the women, but its bioavailability was reduced, which was expressed by a high 3-nitrotyrosine (3-NitroT) concentration. The relation of NO/3-NitroT (rs = 0.811, p < 0.001) in the women and NO/3-NitroT (rs = -0.611, p < 0.001) in the men showed that sex determines endothelial dysfunction. RONS generation in the women simultaneously promoted endothelial regeneration, as demonstrated by a ~1.5-fold increase in circulating progenitor cells. Inflammation-specific variables, such as the neutrophil-to-lymphocyte ratio, the systemic immune inflammation index, and the neutrophil-to-high-density lipoprotein (HDL) ratio, were reduced in the women and showed their diagnostic utility for clinical prognosis in vascular dysfunction, especially the C-reactive-protein-to-HDL ratio (AUC = 0.980, specificity 94.7%, sensitivity 93.3%, OR = 252, 95% CI 65-967, p < 0.001). This study is the first to have revealed sex-specific changes in the oxi-inflammatory response, which can generate the risk of cardiovascular events at an older age.

Real-world PM2.5 exposure induces prostaglandin disruption and low-density lipoprotein oxidation, exacerbating atherogenesis in ApoE−/− mice

Worsened air pollution has been linked to elevated rates of cardiovascular disease (CVD) morbidity and mortality. Atherosclerosis, a shared pathophysiological foundation for various CVD manifestations, plays a crucial role. Although foam cell formation is hypothesized to be a contributing factor, the precise mechanisms by which air pollution accelerates the advancement of atherosclerotic plaques remain unidentified. In this study, an atherosclerosis-susceptible apolipoprotein E-deficient (ApoE−/−) mouse model was employed to examine the influence of real-world environmental PM2.5 exposure on atherosclerosis. Metabolomic analysis was performed to identify potential biomarkers that may play a role in atherogenesis following PM2.5 exposure. Our findings revealed that mice fed a high-cholesterol diet (HCD) exhibited susceptibility to PM2.5 exposure, as evidenced by increased inflammation, enhanced fibrosis, and enlarged foam cell formation in the aorta. The interactive effects between PM2.5 exposure and HCD disrupted the secretion of certain chemokines. The metabolomic data provided additional insights into how PM2.5 exposure alters prostaglandin levels, contributing to the progression of atherosclerotic lesions. These findings enhance our understanding of the pivotal role of arachidonic acid metabolism in the etiology of PM2.5-induced cardiovascular risks and elucidate the mechanisms by which PM2.5 exposure leads to vascular damage in populations with high cholesterol intake.

High glucose enhanced lipoprotein(a) [Lp(a)] oxidation in a manner inhibited by eicosapentaenoic acid (EPA) in vitro

Abstract Background Elevated lipoprotein(a) (Lp(a)) levels are causally and independently associated with increased cardiovascular (CV) risk. Targeted molecular therapies are in development. Levels of oxidized Lp(a) were more predictive of CV events and endothelial dysfunction in type 2 diabetes than non-oxidized forms. EPA administered as icosapent ethyl (IPE) reduced CV events in statin-treated patients (REDUCE-IT) with diabetes and high CV risk. As a fatty acid with multiple conjugated double bonds, EPA inhibits lipoprotein oxidation by a potent lipid-centric scavenging mechanism. We therefore tested the effects of EPA on oxidation of Lp(a) and non-modified LDL under conditions of high glucose to mimic aspects of hyperglycemia in vivo. Methods Lp(a) was enriched to 41% of total ApoB-containing particles from patients with elevated levels by isopycnic centrifugation. Samples of Lp(a) and non-modified LDL were incubated under high glucose (200 mg/dL) conditions at 37°C for 30 min with EPA (50 µM). Samples were then subjected to copper sulfate-induced oxidation (20 µM) monitored by formation of malondialdehyde (MDA) via a colorimetric assay. Results Lp(a) enriched plasma underwent increased oxidation, peaking at 4 hr by 32-fold compared to baseline (0.37 ± 0.04 vs 12.27 ± 0.61 µM, p&amp;lt;0.001) under conditions of high glucose. Non-modified LDL also underwent oxidation in the presence of high glucose with a distinct rate compared to Lp(a), peaking after 3 h (0.28 ± 0.09 vs 10.91 ± 0.93 µM, p&amp;lt;0.001). EPA significantly inhibited both Lp(a) and LDL oxidation in a time-dependent manner. After peak oxidation was achieved in Lp(a) (4 h) and LDL (3 h), EPA inhibited oxidation by 57% (5.29 ± 0.25 µM, p&amp;lt;0.001) and 81% (2.12 ± 0.09 µM, p&amp;lt;0.001), respectively. Conclusions Under hyperglycemic conditions, EPA inhibited oxidation of Lp(a)-enriched plasma and non-modified LDL in a time-dependent manner. The activity of EPA may arise from its lipophilic properties and highly conjugated structure that scavenges free radicals in lipid-concentrated environments. The potent antioxidant activity of EPA may contribute to reduced CV risk in patients with diabetes and elevated Lp(a).

Positive correlation between n-6 : n-3 PUFA ratio intake with serum oxHDL/HDL-c ratio in patients with coronary artery disease.

Coronary artery disease (CAD) is one of the most prevalent cardiovascular diseases where serum lipoprotein oxidation plays a significant role. Polyunsaturated fatty acids (PUFA) n-6 : n-3 unbalance ratio consumption, affects lipoprotein oxidation, and inflammation processes. This study aimed to analyze the relationship between n-6 : n-3 PUFA ratio intake with oxidized lipoproteins in individuals with CAD. A cross-sectional study was performed including 105 subjects (51 diagnosed with CAD and 54 non-CAD) from western Mexico. Dietary information was collected using a habitual day food record. Serum oxidized low-density lipoprotein (oxLDL) and oxidized high-density lipoprotein (oxHDL) concentrations were quantified by enzyme linked immunosorbent assay. CAD subjects had higher oxHDL/HDL cholesterol (HDL-c) ratio [0.102 (0.092-0.112) vs. 0.080 (0.070-0.090), P = 0.004] and oxLDL/LDL cholesterol (LDL-c) ratio [129.2 (108-150.4) vs. 59.7 (39.3-80), P < 0.001] compared to non-CAD subjects. Risk factors associated with CAD were a high n-6 : n-3 PUFA ratio (odds ratio, OR = 2.3, P = 0.046), hypoalphalipoproteinemia in men (OR = 3.2, P = 0.014), moderate/high tobacco index (OR = 6.33, P = 0.003), elevated waist circumference in women (OR = 7, P = 0.004), hypertension (OR = 21.14, P < 0.001), and type 2 diabetes (OR: 25, P < 0.001). The oxHDL/HDL-c ratio was positively associated with the n-6 : n-3 PUFA ratio [r2 = 28.3, B = 0.002 (0.001-0.003), P < 0.001] in CAD patients. This study showed that a higher n-6 : n-3 PUFA ratio intake correlates with higher serum oxHDL/HDL-c in CAD patients.

Age-Related Effects of Olive Oil Polyphenol Ingestion on Oxidation of Low-Density Lipoprotein in Healthy Japanese Men: A Randomized Controlled Double-Blind Crossover Trial.

The function of olive oil polyphenols in suppressing the oxidation of low-density lipoprotein (LDL) is well-known in Europeans. However, it remains unclear whether olive oil polyphenols exert antioxidant effects in Japanese people. The objective of this study was to determine whether the ingestion of olive oil polyphenols suppresses LDL oxidation in the Japanese population and whether this effect depends on age. This randomized controlled double-blind crossover trial with a 2-week washout enrolled 80 healthy Japanese men aged 35-64 years. Participants ingested either 14 g of extra virgin olive oil containing 5.0 mg of olive oil polyphenols (test food) or 14 g of refined olive oil containing 0.3 mg of olive oil polyphenols (control food) for 3 weeks. The primary outcome was oxidized LDL (malondialdehyde-modified LDL; MDA-LDL). Subgroup analyses based on age (35-50 and 51-64 years) were also performed. In all of the participants (35-64 years), there were no significant differences in MDA-LDL between the control and test groups. However, in the 35-50 years subgroup, ingestion of olive oil polyphenols led to a significantly larger reduction in MDA-LDL as compared with the control group (p < 0.025). The significantly lower dietary total polyphenol intake of the 35-50 years subgroup compared to the 51-64 years subgroup suggests that the suppressive function of olive oil polyphenol intake on LDL oxidation in Japanese men is influenced by dietary habits and is more clearly demonstrated in the younger age population with a relatively low total polyphenol intake.

The Role of Inducible Nitric Oxide Synthase in Assessing the Functional Level of Coronary Artery Lesions in Chronic Coronary Syndrome.

Chronic coronary syndrome (CCS) is a long-term manifestation of coronary artery disease, marked by stable but recurring chest pain and myocardial ischemia due to the gradual buildup of atherosclerotic plaques in the coronary arteries. It is a metabolic disorder of coronary arteries characterized by oxidative stress, endothelial dysfunction, inflammation, and hyperlipidemia. The imbalance in oxidative-antioxidative status contributes to stable ischemic heart disease. Oxidative stress involves reactive oxygen and nitrogen species, leading to low-density lipoprotein (LDL) oxidation. Endothelial dysfunction, marked by reduced nitric oxide (NO) bioavailability, is an early onset of CCS, affecting vasodilation, cell proliferation, and inflammatory responses. Enzyme myeloperoxidase (MPO), traditionally considered protective, plays a dual role in initiating and progressing inflammatory diseases. MPO interacts with NO, modulating its catalytic activity. Elevated NO levels inhibit MPO through a reversible complex formation, preventing NO-induced inhibition by inducible nitric oxide synthase (iNOS). MPO also inactivates endothelial nitric oxide synthase (eNOS) and reacts with L-arginine, hindering NO synthesis. The interplay between MPO and NO significantly influences inflammation sites, impacting peroxidation rates and oxidation reactions. Peroxynitrite, a reactive species, contributes to nitration of tyrosine residues and lipid peroxidation. Mechanistic pathways suggest MPO enhances iNOS catalytic activity, influencing CCS development. iNOS, implicated in inflammation and atherosclerosis, is connected to NO regulation. This review analyzes the complex interplay of MPO, iNOS, and NO that affects plaque morphology, oxidative stress, and inflammation, contributing to atherosclerosis progression. Therefore, it is possible that the phenotypes of atherosclerotic plaques, focal and diffuse coronary artery disease, could be defined by the relationship between MPO and iNOS.

Atorvastatin active metabolite and eicosapentaenoic acid inhibit oxidation of lipoprotein(a) [Lp(a)] in a synergistic manner in vitro

Atorvastatin active metabolite and eicosapentaenoic acid inhibit oxidation of lipoprotein(a) [Lp(a)] in a synergistic manner in vitro

Increased vascular deposition of oxidized LDL in untreated juvenile dermatomyositis

BackgroundJuvenile dermatomyositis (JDM) is a systemic vasculopathy associated with metabolic derangements and possible increased risk for premature atherosclerosis. Oxidation of low-density lipoprotein (LDL) in the endothelium is an early step in atherosclerotic plaque formation. It is not known if oxidized LDL is altered in children with untreated JDM. The deposition of oxidized LDL in the vasculature of muscle biopsies (MBx) from patients with untreated JDM and pediatric controls was assessed.FindingsFrozen tissue sections of MRI-directed MBx from 20 female children with untreated JDM and 5 female controls were stained with DAPI and fluorescently labeled antibodies against von Willebrand factor (vWF) and LDL oxidized by copper (oxLDL). Blood vessels were identified by positive vWF staining, and total fluorescence of oxLDL within the vessel walls was measured. Children with untreated JDM had increased deposition of oxLDL in the walls of muscle vasculature compared to healthy children (difference in means ± SEM = 19.86 ± 8.195, p = 0.03). Within the JDM cohort, there was a trend towards increased oxLDL deposition with longer duration of untreated disease (r = 0.43, p = 0.06). There was no significant correlation found between oxLDL deposition and markers of acute JDM disease activity including disease activity scores or muscle enzymes.ConclusionsThis study found increased deposition of oxLDL within blood vessels of children with untreated JDM supporting the concern that these children are at increased risk for premature atherosclerosis from chronic exposure to vascular oxLDL. This study highlights the importance of early diagnosis and treatment initiation to ameliorate cardiovascular damage.

Low-Density Lipoprotein Cholesterol to Triglyceride Ratio and Clinical Outcomes after Acute Ischaemic Stroke or Transient Ischaemic Attack.

Studies showed that low-density lipoprotein cholesterol (LDL-C) to triglyceride (TG) ratio could be used as a predictive parameter of low-density lipoprotein oxidation in vivo and the level of small dense LDL-C. However, whether LDL-C/TG ratio is associated with stroke prognosis remains unclear. We investigated the associations of LDL-C/TG ratio with outcomes in patients with acute ischaemic stroke (AIS) or transient ischaemic attacks (TIA) and explored whether it produced more predictive value than LDL-C and TG. Data were derived from the Third China National Stroke Registry (CNSR-III). Multivariable Cox regression for stroke recurrence, composite vascular events and all-cause death and logistic regression for the poor functional outcome (modified Rankin Scale score 3-6) were used. A total of 14123 patients were included. After adjusting for confounding factors, quartile 4 of LDL-C/TG ratio was associated with an increased risk of recurrent stroke (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.03-1.56), composite vascular events (HR,1.23; 95% CI, 1.00-1.52), death (HR,1.70; 95% CI, 1.13-2.54) and poor functional outcome (odds ratio, 1.34; 95% CI, 1.12-1.61) at 3 months follow-up compared with quartile 1. We also found that quartile 4 of LDL-C and TG was positively and negatively associated with poor functional outcome at 3 months, respectively. LDL-C/TG ratio performed better than LDL-C or TG in predicting clinical outcomes. LDL-C/TG ratio was associated with the risk of stroke recurrence, composite vascular events, death and poor functional outcome in patients with AIS or TIA.

Novel Biomarkers in Vascular Diseases: From Discovery to Clinical Translation

Endothelial activation as well as dysfunction is a major factor in atherosclerosis, cardiovascular disorders, and cardiorenal syndrome. Endothelial dysfunction is additionally associated with metabolic syndrome as well as type II diabetes. The hunt for distinctive as well as sensitive biomarkers of endothelial activity and dysfunction may have substantial therapeutic consequences. This review pinpoints the variations in biomarkers that occur between endothelial activation and endothelial dysfunction in cardiovascular illnesses, and then briefly highlights the most significant biomarkers of endothelial activation. Biomarkers of endothelial activation consist of endothelial adhesion molecules, as well as cytokines, and C-reactive protein, along with CD62E++/E-selectin activated endothelial microparticles, and oxidation of low-density lipoproteins, together with asymmetric dimethylarginine as well as endocan. This study also includes an update on the new biomarkers of endothelial dysfunction, such as matrix metalloproteinases (MMP) (e.g., MMP-7, MMP-9), along with ANGPTL2, and endoglin, together with annexin V++ endothelium apoptotic microparticles, and serum homocysteine. Finally, this study stresses the limits of biomarkers of endothelium activation and dysfunction in clinical situations.

Scavenger Receptors: Different Classes and their Role in the Uptake of Oxidized Low-Density Lipoproteins

Oxidation of lipoproteins marks a fundamental early phase in atherosclerosis development, a condition distinguished by plaque build-up in the arteries. It is widely accepted that the oxidation of low-density lipoprotein (LDL) plays a pivotal role in atherosclerosis progression. Oxidized LDL (Ox-LDL) exhibits numerous atherogenic characteristics, leading to endothelial dysfunction, the creation of foam cells, and inflammation in the arterial wall. The crucial interaction between Ox-LDL and specific receptors on endothelial cells is key to initiating these processes. In this article, we're going to delve into the various LDL receptors that play a crucial part in the uptake and metabolism of LDL, emphasizing their significance in the development of atherosclerosis. The Cochrane database, Embase, PubMed, Scopus, Google Scholar, Ovid, and other databases were thoroughly searched for works addressing scavenger receptors to explore how both native LDL (nLDL) and Ox-LDL engage with these receptors, facilitating the formation and progression of atherosclerotic plaques. We'll then proceed to a more detailed examination of the complex role scavenger receptors play in the uptake and internalization of oxidized low-density lipoproteins (Ox-LDL), and their vital role in the onset of diseases. The review will further cover the identification, categorization, and roles of scavenger receptors, along with their molecular mechanisms. Grasping the complexity of these receptor-ligand interactions is critical for the creation of focused treatments to fight against pathologic conditions such as atherosclerosis and its related health scenarios.

Lipoprotein Oxidation, Genetic Expression and Polymorphism of Apo A and B Gene in Patients with Coronary Artery Disease in A Pakistani Punjabi Population

Oxidative alterations of lipoproteins and numerous polymorphism locations in the apolipoprotein A1 (APOA1) and B (APOB) genes have been identified as risk factors for cardiovascular events. The aim of the study was to investigate the gene expression and the role of APOA and B gene polymorphisms in coronary artery disease (CAD) and their relationship with lipid profiles, oxidized High Density Lipoprotein (oxHDL), and oxidized Low Density Lipoprotein (oxLDL) in the Punjabi Pakistani population. A total of 200 subjects were included, of which 135 were diagnosed as having CAD and 65 were not. The lipid profile, oxHDL, and oxLDL were measured through the calorimetric method and ELISA, respectively. Quantitative variables represented by mean ± SD for normally distributed data. Gene expression was done on cDNA through Real-time PCR. Genotyping of APOA1 (rs670, rs5069) and APOB (rs693, rs11279109) were performed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism), and gel electrophoresis was used for band visualization. Our findings showed that the oxHDL, oxLDL, APOA, B gene expression and Del genotype of APOB rs11279109 was significantly increased in CAD cases. In addition, significant high levels of oxHDL, oxLDL, serum cholesterol, VLDL, TG, and cholesterol/HDL ratio has been shown to be associated with CAD. APOB (rs11279109) has a significant impact on dyslipidemia and exhibit a higher risk of CAD (OR=3.97) while, APOB (rs693), APOA1 (rs670), (rs5069) possesses a lower risk of CAD in the population. Hence, levels of oxHDL and oxLDL as well as ApoA1 and APOB genotyping could be useful in identifying individuals who are at risk of CAD.

Synergistic Anti-Inflammatory Activity of Lipid-Free Apolipoprotein (apo) A-I and CIGB-258 in Acute-Phase Zebrafish via Stabilization of the apoA-I Structure to Enhance Anti-Glycation and Antioxidant Activities.

CIGB-258, a 3 kDa peptide from heat shock protein 60, exhibits synergistic anti-inflammatory activity with apolipoprotein A-I (apoA-I) in reconstituted high-density lipoproteins (rHDLs) via stabilization of the rHDL structure. This study explored the interactions between CIGB-258 and apoA-I in the lipid-free state to assess their synergistic effects in the structural and functional enhancement of apoA-I and HDL. A co-treatment of lipid-free apoA-I and CIGB-258 inhibited the cupric ion-mediated oxidation of low-density lipoprotein (LDL) and a lowering of oxidized species in the dose-responsive manner of CIGB-258. The co-presence of CIGB-258 caused a blue shift in the wavelength of maximum fluorescence (WMF) of apoA-I with protection from proteolytic degradation. The addition of apoA-I:CIGB-258, with a molar ratio of 1:0.1, 1:0.5, and 1:1, to HDL2 and HDL3 remarkably enhanced the antioxidant ability against LDL oxidation up to two-fold higher than HDL alone. HDL-associated paraoxonase activities were elevated up to 28% by the co-addition of apoA-I and CIGB-258, which is linked to the suppression of Cu2+-mediated HDL oxidation with the slowest electromobility. Isothermal denaturation by a urea treatment showed that the co-presence of CIGB-258 attenuated the exposure of intrinsic tryptophan (Trp) and increased the mid-points of denaturation from 2.33 M for apoA-I alone to 2.57 M for an apoA-I:CIGB-258 mixture with a molar ratio of 1:0.5. The addition of CIGB-258 to apoA-I protected the carboxymethyllysine (CML)-facilitated glycation of apoA-I with the prevention of Trp exposure. A co-treatment of apoA-I and CIGB-258 synergistically safeguarded zebrafish embryos from acute death by CML-toxicity, suppressing oxidative stress and apoptosis. In adult zebrafish, the co-treatment of apoA-I+CIGB-258 exerted the highest anti-inflammatory activity with a higher recovery of swimming ability and survivability than apoA-I alone or CIGB-258 alone. A co-injection of apoA-I and CIGB-258 led to the lowest infiltration of neutrophils and interleukin (IL)-6 generation in hepatic tissue, with the lowest serum triglyceride, aspartate transaminase, and alanine transaminase levels in plasma. In conclusion, the co-presence of CIGB-258 ameliorated the beneficial functionalities of apoA-I, such as antioxidant and anti-glycation activities, by enhancing the structural stabilization and protection of apoA-I. The combination of apoA-I and CIGB-258 synergistically enforced the anti-inflammatory effect against CML toxicity in embryos and adult zebrafish.

Cardiovascular disease: extraintestinal manifestation of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a spectrum of diseases characterized by the interplay of the aberrant immune system, genetic factors, environmental factors, and intestinal microbiota, resulting in relapsing inflammation of the gastrointestinal tract. Underlying pro-inflammatory state and immune dysregulation act as a catalyst for increasing the likelihood of developing extraintestinal manifestations, including cardiovascular diseases (CVD) like atherosclerosis, pericarditis, myocarditis, venous and arterial thromboembolism, arrhythmias, despite a lower prevalence of classic CVD risk factors, like high body mass index or dyslipidemia compared to the general population. Chronic inflammation damages endothelium resulting in the recruitment of inflammatory cells, which induce cytotoxicity, lipoprotein oxidation, and matrix degradation, which increases the risk of atherosclerosis. Additionally, intestinal dysbiosis disrupts the intestinal mucosal barrier, releasing endotoxins and lipopolysaccharides into circulation, further exaggerating the atherosclerotic process. Abnormal collagen metabolism and alteration of nitric oxide-mediated vasodilation lead to blood pressure dysregulation in patients with IBD. Therefore, it is essential to make lifestyle modifications like smoking cessation, dietary changes, and increasing physical activity with adherence to medication to mitigate the risk of developing CVD in patients with IBD. This article reviews the potential links between IBD and the increased risk of CVD in such individuals.

Targeting macrophages with multifunctional nanoparticles to detect and prevent atherosclerotic cardiovascular disease.

Despite the emergence of novel diagnostic, pharmacological, interventional, and prevention strategies, atherosclerotic cardiovascular disease remains a significant cause of morbidity and mortality. Nanoparticle (NP)-based platforms encompass diverse imaging, delivery, and pharmacological properties that provide novel opportunities for refining diagnostic and therapeutic interventions for atherosclerosis at the cellular and molecular levels. Macrophages play a critical role in atherosclerosis and therefore represent an important disease-related diagnostic and therapeutic target, especially given their inherent ability for passive and active NP uptake. In this review, we discuss an array of inorganic, carbon-based, and lipid-based NPs that provide magnetic, radiographic, and fluorescent imaging capabilities for a range of highly promising research and clinical applications in atherosclerosis. We discuss the design of NPs that target a range of macrophage-related functions such as lipoprotein oxidation, cholesterol efflux, vascular inflammation, and defective efferocytosis. We also provide examples of NP systems that were developed for other pathologies such as cancer and highlight their potential for repurposing in cardiovascular disease. Finally, we discuss the current state of play and the future of theranostic NPs. Whilst this is not without its challenges, the array of multifunctional capabilities that are possible in NP design ensures they will be part of the next frontier of exciting new therapies that simultaneously improve the accuracy of plaque diagnosis and more effectively reduce atherosclerosis with limited side effects.