Effects of D-4F on Vasodilation and Vessel Wall Thickness in Hypercholesterolemic LDL Receptor–Null and LDL Receptor/Apolipoprotein A-I Double-Knockout Mice on Western Diet

Abstract

Abstract-Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor-null (Ldlr Ϫ/Ϫ ) mice and transgenic sickle cell disease mice. Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr Ϫ/Ϫ mice and Ldlr Ϫ/Ϫ /apoA-I null (apoA-I Ϫ/Ϫ ), double-knockout mice. Ldlr Ϫ/Ϫ and Ldlr Ϫ/Ϫ / apoA-I Ϫ/Ϫ mice were fed Western diet (WD) with and without D-4F. Oral D-4F restored endothelium-and endothelial NO synthase (eNOS)-dependent vasodilation in direct relationship to duration of treatments and reduced wall thickness in as little as 2 weeks in vessels with preexisting disease in Ldlr Ϫ/Ϫ mice. D-4F had no effect on total or HDL cholesterol concentrations but reduced proinflammatory HDL levels. D-4F had no effect on plasma myeloperoxidase concentrations but reduced myeloperoxidase association with apoA-I as well as 3-nitrotyrosine in apoA-I. D-4F increased endothelium-and eNOS-dependent vasodilation in Ldlr Key Words: cardiovascular diseases Ⅲ hypercholesterolemia Ⅲ lipoproteins Ⅲ nitric oxide synthase Ⅲ vasodilation E ndothelial cells play an important role in maintaining vascular health. One of the earliest physiological and most sensitive changes in hypercholesterolemia is loss of endothelium-and endothelial NO synthase (eNOS)-dependent vasodilation, which appears to occur before structural changes in the vessel wall. 1,2 In a prospective human study, angiography was used to observe impaired endothelium-dependent vasodilation in coronary arteries and was found to be a strong prognostic indicator of vascular pathology. 3 Such findings, 3 as well as those from others, 4,5 support the concept that endothelium-dependent vasodilation provides important insights into the atherogenic state of the vessel wall.We previously reported L-4F, when administered by IP injection, increased eNOS-dependent vasodilation of small arteries from hypercholesterolemic Ldlr Ϫ/Ϫ mice and from transgenic sickle cell mice. 6 D-4F is the same as L-4F, except it is synthesized from D-amino acids. In the D conformation, 4F is resistant to metabolism compared with 4F synthesized from L-amino acids, which is rapidly degraded after oral administration. 8 Oral D-4F reduced lesions in Ldlr Ϫ/Ϫ mice fed WD by more than 79% by restoring HDL function without significantly altering cholesterol or HDL cholesterol levels. 7 Interestingly, D-4F also reduced lesions in apoE Ϫ/Ϫ mice, which were hypercholesterolemic from birth. 7 However, to date, no studies have been performed to determine Original

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

“…The values shown are the Mean ± SD. *P < 0.05. tein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they have efficacy in a wide range of inflammatory conditions (10, 13), including, in animal models of dyslipidemia (10,11,42,43), diabetes and vascular inflammation (44)(45)(46)(47)(48), renal disease (12,49), sepsis (50), and Alzheimer's disease (51). Our studies demonstrate that apoA-I mimetic peptides are very effective in preventing the development of tumors (Figs.…”

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…supra) and subsequent replacement fibrosis, resulting in improved left ventricular function. The anti-inflammatory and antifibrotic effects of HDL are supported by findings in apo A-I knockout mice, which are associated with increased inflammatory cells and collagen deposition in the lung (Wang et al 2010), and from observations with the mimetic apo A-I peptide 4F demonstrating an L-4F-mediated decreased endothelial cell matrix production (Ou et al 2005). Since cardiac NADPH oxidases play a predominant role in the development of diabetic cardiomyopathy (Guo et al 2007;Wold et al 2006) and in diabetic cardiac remodelling (Li et al 2010b), decreased cardiac NADPH oxidase activity following apo A-I transfer (Van Linthout et al 2009) may be a critical mediator of reduced cardiac oxidative stress and subsequent fibrosis in the myocardium.…”

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

“…2E). However, it remains possible that the mimetic peptides interact with the endogenous apoE-HDL particles to prevent their turnover and eventually increase their overall amounts (43,45) and in this way promote A␤ degradation rather than by the direct cholesterol lowering effect of the 4F peptide. To evaluate this possibility, we performed the same assay in apoE-deficient microglia.…”