Enhanced Lipid Peroxidation and Platelet Activation as Potential Contributors to Increased Cardiovascular Risk in the Low‐HDL Phenotype

Abstract

BackgroundLow high‐density lipoprotein (HDL) levels are major predictors of cardiovascular (CV) events, even in patients on statin treatment with low‐density lipoprotein (LDL) at target. In animal models HDLs protect LDL from oxidation and blunt platelet activation. Our study aimed to examine whether HDL levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis.Methods and ResultsUrinary 8‐iso‐PGF2α and 11‐dehydro‐TXB2, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/dL, and in 47 CHD patients with HDL >35 mg/dL. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/dL showed significantly higher urinary 8‐iso‐PGF2α (median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine, P=0.019) and 11‐dehydro‐TXB2 (563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine, P=0.0001) than patients with higher HDL. A direct correlation was found between urinary 8‐iso‐PGF2α and 11‐dehydro‐TXB2 in the entire group of patients (ρ=0.77, P<0.0001). HDL levels were inversely related to both 8‐iso‐PGF2α (ρ=−0.32, P=0.001) and 11‐dehydro‐TXB2 (ρ=−0.52, P<0.0001). On multiple regression, only 8‐iso‐PGF2α (β=0.68, P<0.0001) and HDL level (β=−0.29, P<0.0001) were associated with urinary 11‐dehydro‐TXB2 excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase.ConclusionsA low HDL phenotype, both in CHD patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low HDL with increased CV risk.

Modification of platelet proteins by 4-hydroxynonenal: Potential Mechanisms for inhibition of aggregation and metabolism

“…The process of platelet aggregation involves the liberation of plasma membrane arachidonic acid which generates both enzymatic and non-enzymatic lipid peroxidation products [30–32]. The non-enzymatic lipid peroxidation product 4-HNE is a marker of oxidative stress, and has been associated with a number of different pathologies [5–9].…”

High‐Density Lipoprotein: A Novel Target for Antirestenosis Therapy

“…Platelet activation has been reported after coronary angioplasty, especially in DES, and is correlated with restenosis and the risk of late stent thrombosis . Platelet activation is inversely correlated with HDL levels in human, suggesting that HDL has antiplatelet properties . In vitro , HDL can interfere with LDL and ox‐LDL‐induced platelet activation .…”

“…105 Platelet activation is inversely correlated with HDL levels in human, suggesting that HDL has antiplatelet properties. 106 In vitro, HDL can interfere with LDL and ox-LDL-induced platelet activation. 107,108 In animal models, infusion of apoA-I mimetic peptide into rats or mice inhibits platelet aggregation.…”

Kolaviron, a biflavonoid fraction from Garcinia kola, protects against isoproterenol-induced injury by mitigating cardiac dysfunction and oxidative stress in rats

“…This is usually followed by numerous pathophysiological and biochemical changes including lipid peroxidation (LPO) and hyperlipidemia [3]. It has also been suggested that heart failure subsequent to myocardial infarction may be associated with antioxidant deficit as well as increased myocardial oxidative stress [4]. Isoproterenol (ISO) (Figure 1) is a potent synthetic catecholamine that causes the development of infarct-like lesions when injected into animals and resembles human myocardial infarction [5].…”