Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia

2007 ◽  
Vol 293 (3) ◽  
pp. R1110-R1119 ◽  
Author(s):  
Phoebe A. Stapleton ◽  
Adam. G. Goodwill ◽  
Milinda E. James ◽  
Jefferson C. Frisbee
Keyword(s):  
Skeletal Muscle ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Nordihydroguaiaretic Acid ◽  
Arachidonic Acid Metabolism ◽  
Density Lipoprotein Receptor ◽  
Oxide Synthase ◽  
Cytochrome P 450

With most cardiovascular disease risk factors, endothelium-dependent dilation of skeletal muscle resistance arterioles is compromised, although with hypercholesterolemia, impairments to reactivity are not consistently observed. Using apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion male mouse models of hypercholesterolemia at 20 wk of age, we tested the hypothesis that arteriolar dilation would be maintained due to an increased stimulus-induced production of dilator metabolites via cyclooxygenase and cytochrome P-450 epoxygenase pathways. Arterioles from both strains demonstrated mild reductions in dilation to hypoxia and acetylcholine versus responses in C57/Bl/6J (C57) controls. However, although inhibition of nitric oxide synthase (NOS) attenuated dilation in arterioles from C57 controls, this effect was absent in ApoE or LDLR strains. In contrast, cyclooxygenase-dependent portions of dilator reactivity were maintained across the three strains. Notably, although combined NOS and cyclooxygenase inhibition abolished arteriolar responses to hypoxia and acetylcholine in C57 controls, significant reactivity remained in ApoE and LDLR strains. Whereas inhibition of cytochrome P-450 ω-hydroxylase and epoxygenases had no effect on this residual reactivity in ApoE and LDLR strains, inhibition of 12/15-lipoxygenase with nordihydroguaiaretic acid abolished the residual reactivity. With both hypoxic and methacholine challenges, arteries from ApoE and LDLR strains demonstrated an increased production of both 12( S)- and 15( S)-hydroxyeicosatetraenoic acid, end products of arachidonic acid metabolism via 12/15-lipoxygenase, a response that was not present in C57 controls. These results suggest that with development of hypercholesterolemia, mechanisms contributing to dilator reactivity in skeletal muscle arterioles are modified such that net reactivity to endothelium-dependent stimuli is largely intact.

Abstract 15805: PCSK9 R46L, Lower LDL and Cardiovascular Disease Risk in Familial Hypercholesterolemia

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Alexis Baass
Keyword(s):  
Cardiovascular Risk ◽  
Familial Hypercholesterolemia ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Monogenic Disease ◽  
Loss Of Function ◽  
Lipid Clinic ◽  
Density Lipoprotein Receptor

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a down-regulator of the low density lipoprotein receptor (LDLR). Familial hypercholesterolemia (FH) is a autosomal monogenic disease associated with high LDL-C concentration and cardiovascular risk. Hypothesis: This study aimed to examine whether the PCSK9 R46L loss of function mutation found in a cohort of FH patients will be associated with lower LDL-C and cardiovascular risk. Methods: We studied FH patients attending the IRCM Lipid Clinic and whose DNA genotyping was positive for LDLR mutations. The presence of the PCSK9 loss of function R46L missense mutation was determined among a cohort of 582 FH patients by sequencing. Results: Frequency of the R46L variant was 3%. Comparison of their lipid profile showed that carriers had significantly reduced LDL-C (11%, p<0.001), TC (9%, p<0.01), ApoB (10%, p<0.01) and non-HDL (12%, p<0.001) concentrations compared to non-carriers. The analysis of physical xanthomata among both groups, showed a decreased average number of xanthoma per individual in R46L carriers (0.33 and 0.76 respectively, p<0.001). Importantly, the R46L mutation was associated with a significant 66% (p=0.05) lower risk of cardiovascular events compared to non-carriers. Conclusion: Our study showed that the presence of the PCSK9 loss of function R46L mutation in the genotype of FH patients is beneficial for the lipid homeostasis and down-regulate the effect of the LDLR mutation in terms of accumulation of LDL-C, ApoB , total cholesterol, non-HDL and thereby, lowers the coronary heart disease risk of PCSK9 LOF mutation carriers. It is therefore very likely that anti-PCSK9 therapy will be useful in reducing cardiovascular risk in FH patients.

scholarly journals ApoC-III Glycoforms Are Differentially Cleared by Hepatic TRL (Triglyceride-Rich Lipoprotein) Receptors

2019 ◽  
Vol 39 (10) ◽  
pp. 2145-2156 ◽  
Author(s):  
Natalie C. Kegulian ◽  
Bastian Ramms ◽  
Steven Horton ◽  
Olgica Trenchevska ◽  
Dobrin Nedelkov ◽  
...  
Keyword(s):  
Relative Abundance ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
Plasma Triglyceride ◽  
Wild Type ◽  
Triglyceride Rich Lipoprotein ◽  
Density Lipoprotein Receptor

Objective: ApoC-III (apolipoprotein C-III) glycosylation can predict cardiovascular disease risk. Higher abundance of disialylated (apoC-III 2 ) over monosialylated (apoC-III 1 ) glycoforms is associated with lower plasma triglyceride levels. Yet, it remains unclear whether apoC-III glycosylation impacts TRL (triglyceride-rich lipoprotein) clearance and whether apoC-III antisense therapy (volanesorsen) affects distribution of apoC-III glycoforms. Approach and Results: To measure the abundance of human apoC-III glycoforms in plasma over time, human TRLs were injected into wild-type mice and mice lacking hepatic TRL clearance receptors, namely HSPGs (heparan sulfate proteoglycans) or both LDLR (low-density lipoprotein receptor) and LRP1 (LDLR-related protein 1). ApoC-III was more rapidly cleared in the absence of HSPG (t 1/2 =25.4 minutes) than in wild-type animals (t 1/2 =55.1 minutes). In contrast, deficiency of LDLR and LRP1 (t 1/2 =56.1 minutes) did not affect clearance of apoC-III. After injection, a significant increase in the relative abundance of apoC-III 2 was observed in HSPG-deficient mice, whereas the opposite was observed in mice lacking LDLR and LRP1. In patients, abundance of plasma apoC-III glycoforms was assessed after placebo or volanesorsen administration. Volanesorsen treatment correlated with a statistically significant 1.4-fold increase in the relative abundance of apoC-III 2 and a 15% decrease in that of apoC-III 1 . The decrease in relative apoC-III 1 abundance was strongly correlated with decreased plasma triglyceride levels in patients. Conclusions: Our results indicate that HSPGs preferentially clear apoC-III 2 . In contrast, apoC-III 1 is more effectively cleared by LDLR/LRP1. Clinically, the increase in the apoC-III 2 /apoC-III 1 ratio on antisense lowering of apoC-III might reflect faster clearance of apoC-III 1 because this metabolic shift associates with improved triglyceride levels.

scholarly journals rs2569190A>G in CD14 is Independently Associated with Hypercholesterolemia: A Brief Report

2019 ◽  
Vol 6 (4) ◽  
pp. 37 ◽  
Author(s):  
Ali Salami ◽  
Christy Costanian ◽  
Said El Shamieh
Keyword(s):  
Disease Risk ◽  
Middle Eastern ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Multiethnic Population ◽  
Cluster Of Differentiation

Many studies have assessed the implication of cluster of differentiation 14 (CD14) molecules and its single nucleotide polymorphism rs2569190A>G with different complex diseases, such as diabetes and cardiovascular diseases (CVDs). In this study, we investigated the association of rs2569190A>G in CD14 with cardiovascular disease risk factors (hypercholesterolemia and hypertension) in 460 individuals from the general Lebanese population (Middle Eastern multiethnic population). Using a multiple logistic regression model adjusted for six covariates (under additive and recessive assumptions), we found that the G allele of rs2569190 in CD14 was associated with increased levels of total cholesterol (OR = 3.10, p = 0.009), low-density lipoprotein cholesterol (OR = 3.87, p = 0.003), and decreased levels of high-density lipoprotein cholesterol (OR = 0.38, p = 0.001). In contrast, no significant relationship was found with hypertension. Thus, we concluded that rs2569190G in CD14 is associated with a higher risk of developing hypercholesterolemia.

New Insights into Cardiovascular Disease Risk in Subjects with Visceral Obesity

2003 ◽  
Vol 15 (1_suppl) ◽  
pp. S37-S40 ◽  
Author(s):  
AP James ◽  
K Slivkoff-Clark ◽  
JCL Mamo
Keyword(s):  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Visceral Obesity ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Insulin Resistant ◽  
Essentially Normal ◽  
Ldl Particles ◽  
Chylomicron Metabolism

Obese insulin resistant individuals often present with a dyslipidemic phenotype characterised by hypertriglyceridemia, low HDL cholesterol levels, essentially normal total- and LDL-cholesterol, but a propensity for smaller, denser LDL particles. We have reported that concentrations of chylomicrons are two to three folds greater than in age-matched lean controls. We have recently observed that in lean free-living subjects the flux of chylomicrons over a 12h period was just 25% greater in these subjects than basal chylomicron production. Constitutive secretion of chylomicrons appears to be of greater relevance to arterial exposure than postprandial fluctuations. Insulin critically regulates the metabolism of very low density lipoprotein (VLDL) and hence it would be expected that the hormone is also involved in the regulation of chylomicron metabolism. Impaired insulin action may therefore be responsible for the associated hyperchylomicronaemia. In this review we examine the hypothesis that insulin chronically modulates chylomicron metabolism and present evidence suggesting that hyperchylomicronaemia primarily results from impaired chylomicron production.

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