Lipoprotein Metabolism and Atherosclerosis

Purpose: Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 G > A or Val108 > 158Met or rs4680 G > A influences COMT enzyme activity. The three phenotypes of the COMT enzyme activities include COMT A/A with low enzyme activity, COMT A/G with medium enzyme activity and COMT G/G with high enzyme activity. The Met allele is associated with low enzymatic activity resulting in higher levels of prefrontal dopamine. Conversely, the Val allele is associated with high enzymatic activity and lower levels of prefrontal dopamine. The Met allele has been associated with several psychiatric disorders such as panic disorder. Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and coronary artery diseases risk, but the results are inconclusive. Therefore our study was aimed to explore the association between COMT Val158Met polymorphism and the risk of coronary artery disease in India. Methology: This study was conducted on 100 clinically confirmed cases of coronary artery diseases and 100 healthy controls. COMT Val158Met genotyping was performed by allele-specific polymerase chain reaction (AS-PCR). Results: A significant correlation was observed in the COMT Val158Met genotype distribution between the coronary artery disease cases and healthy controls (p = 0.008). The frequencies of all three genotypes, GG, GA, AA, reported in the CAD patients were 10%, 70%, and 20%, and 30%, 60%, and 10% in the healthy controls respectively. An increased risk of coronary artery disease was observed in the codominant inheritance model for COMT-GA vs. GG genotype with an OR of 3.5, 95% CI (1.58–7.74) p = 0.002) and COMT-AA vs. GG genotype with an OR of 6.0 95% CI (2.11–17.3) p = 0.003). The higher risk of coronary artery disease was observed in the dominant inheritance model for COMT (GA + AA) vs. GG genotype (OR 3.85, 95% CI 1.76–8.4, p < 0.007), whereas a non-significant association was found in recessive model for COMT (GG + GA vs. AA) (OR = 2.01, 95% CI (0.86–4.7) p = 0.72). The results indicated that A allele significantly increased the risk of coronary artery disease compared to the G allele (OR = 1.8, 95% CI (1.20–2.67) p = 0.004). COMT Val158Met polymorphism leads to a 6.0, 3.5 and 1.8-fold increased risk of developing coronary artery disease in the Indian population and providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusions: It is concluded that COMT-AA genotype and A allele are significantly associated with an increased susceptibility to coronary artery disease in Indian population. A larger sample size can be the key to progress in establishing the genetic co-relationship of COMT polymorphism and cardiovascular disease. Full article

Introduction: Oxidized low-density lipoprotein (ox-LDL) is considered a main biomarker of oxidative stress, a common characteristic in end stage renal disease. We examined the relationship between ox-LDL serum concentrations and cardiovascular disease in permanent hemodiafiltration therapy patients. Methods: Ox-LDL values were measured by ELISA and were corrected for LDL-cholesterol (LDL-C) in 96 participants and in 45 healthy control subjects. We performed chi-square tests and adjusted models for the role of ox-LDL on cardiovascular morbidity including coronary artery disease, left ventricular hypertrophy, systolic, diastolic dysfunction and peripheral arterial disease. Results: ox-LDL/LDL-C values were significantly higher in patients than in control group (p = 0.02), due to increased ox-LDL serum levels rather than to low LDL-C. The unadjusted relationship between high ox-LDL/LDL-C and low ejection fraction was found significant (x² = 9.04, p = 0.003), although the association with the other cardiovascular manifestations was found non-significant. In the adjusted model for the prediction of systolic cardiac dysfunction, high ox-LDL/LDL-C, old age and non-administration of vitamin D supplementation during dialysis session were found to be significant predictors after adjustment to the confounder. Moreover, the association between systolic cardiac dysfunction and non-administration of vitamin D derivatives during dialysis sessions was found significant (x² = 6.9, p = 0.008). Conclusions: This study showed a significant association between high ox-LDL and systolic cardiac dysfunction in permanent hemodiafiltration therapy patients. This relationship seems to be influenced by aging and pharmaceutical therapy during dialysis sessions, including vitamin D derivatives. Full article

Purpose: The low-density lipoprotein receptor is responsible for the binding and uptake of plasma LDL particles and plays a critical role in maintaining cellular cholesterol homeostasis. LDLR gene SNP rs688 has been reported to be associated with increased plasma total and LDL cholesterol in several populations and can lead to elevated plasma LDL levels, resulting in an increased risk for atherosclerosis and coronary artery disease. This study aimed to explore genetic LDLR variant rs688 for its potential roles in coronary artery disease. Methodology: This study recruited 200 coronary artery disease patients and 200 healthy individuals. Genotyping of LDLR-rs688C > T gene variations was performed using the allele specific PCR method. Correlation of LDLR-rs688C > T gene variants with different clinicopathological features of coronary artery disease patients was performed. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of this microRNA polymorphism with coronary artery disease risk. Results: A significant difference was observed in genotype distribution among the coronary artery disease and matched healthy controls (p = 0.003). The frequencies of all three genotypes CC, CT, TT reported in the patient samples were 14%, 65% and 21% and in the healthy controls samples were 18%, 73% and 9%, respectively. The increased risk of developing CAD in Indian patients was found to be associated with LDLR rs688 TT genotype (OR = 3.0, 95% CI, 1.43 × 6.2; p = 0.003) RR 1.87 (1.20–2.91) p = 0.0037) and also the increased risk of developing CAD was reported to be associated with LDLR rs688 T allele (OR = 0.74, 95% CI, 1.57–0.97; p = 0.03) RR 0.85 (0.73–0.99) p = 0.03) compared to the C allele. Therefore, it was observed that more than a 3.0- and 0.74-fold increase risk of developing CAD was associated with TT genotype and T allele in Indian coronary artery disease patients. Conclusion: The findings indicated that LDLR rs688 TT genotype and T allele are associated with an increased susceptibility to coronary artery disease patients. LDLR-rs688C > T gene variation can be used as a predisposing genetic marker for coronary artery disease. Further studies with larger sample sizes are necessary to confirm our findings. Full article

Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti-atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies. Full article

Experimental and clinical data indicate that the initiation and progress of atherosclerosis and its clinical manifestations are first caused by circulating apoB-100 lipoproteins that enter and are retained in the arterial intima. Extracellular sulfated proteoglycans (PGs) of the intima are the retention agents. The PGs also initiate physical and biochemical lipoprotein degradation with the production of bioactive, lipid products that trigger an inflammatory response that leads to atherosclerosis. There are many simple methods for measuring abnormalities of circulating lipoproteins and their relation to atherosclerotic cardiovascular disease (ACVD). However, limited research aims to evaluate procedures that could report quantitatively about the contribution of the interaction of apoB-100 lipoprotein-arterial intima PGs to clinical manifestation of ACVD. In the present review we discuss observations indicating that simple ex vivo evaluation of the affinity of apoB-100 lipoproteins for arterial PGs and glycosaminoglycans (GAGs) can give an indication of its association with clinical manifestations of atherosclerosis. In addition, we discuss molecular and cellular aspects of the apoB-100 lipoproteins association with arterial PGs that are related to atherogenesis and that support the experimental framework behind the current “Response-to-Retention” hypothesis of atherosclerosis. Full article

Apolipoprotein (apo) E stands out among plasma apolipoproteins through its unprecedented ability to protect against atherosclerosis. Although best recognized for its ability to mediate plasma lipoprotein clearance in the liver and protect against macrophage foam cell formation, our recent understanding of the influence that apoE can exert to control atherosclerosis has significantly widened. Among apoE’s newfound athero-protective properties include an ability to control exaggerated hematopoiesis, blood monocyte activation and aortic stiffening in mice with hyperlipidemia. Mechanisms responsible for these exciting new properties extend beyond apoE’s ability to prevent cellular lipid excess. Rather, new findings have revealed a role for apoE in regulating microRNA-controlled cellular signaling in cells of the immune system and vascular wall. Remarkably, infusions of apoE-responsive microRNA mimics were shown to substitute for apoE in protecting against systemic and vascular inflammation to suppress atherosclerosis in mice with hyperlipidemia. Finally, more recent evidence suggests that apoE may control the release of microvesicles that could modulate cellular signaling, inflammation and atherosclerosis at a distance. These exciting new findings position apoE within the emerging field of intercellular communication that could introduce new approaches to control atherosclerosis cardiovascular disease. Full article

Lipoprotein apheresis (LA) is a therapeutic approach to save the lives of patients who are at an extremely high risk of developing cardiovascular events (CVE), especially after all other therapeutic options were not tolerated, or appeared not to be effective enough. Homozygous familial hypercholesterolemia represents a clear indication to start LA therapy. Another recognized indication is a severe hypercholesterolemia, which induced CVE, often in association with other risk factors. In the last years, an expressive elevation of lipoprotein(a) (Lp(a)) emerged as an indication for LA. In Germany, progress of atherosclerosis should have been documented before the permission to start LA therapy is given in these patients. Usually, all LA methods acutely decrease both LDL-C and Lp(a). However, specific columns which reduce only Lp(a) are available. Case reports and prospective observations comparing the situation before and during LA therapy clearly show a high efficiency with respect to the reduction of CVE, especially in patients with high Lp(a) levels. PCSK9 inhibitors may reduce the need for LA in patients with heterozygous or polygenetic hypercholesterolemia, but in some patients, a combination of these drugs with LA will be necessary. In the future, an antisense oligonucleotide against apolipoprotein(a) may offer an alternative therapeutic approach. Full article