Showing papers on "Fatty streak published in 2016"

Atherosclerotic cardiovascular disease: a review of initiators and protective factors.

Abstract: Atherosclerotic cardiovascular disease (CVD) is a collective term comprising of a group of disorders of the heart and blood vessels. These diseases are the largest cause of morbidity and premature death worldwide. Coronary heart disease and cerebrovascular disease (stroke) are the most frequently occurring diseases. The two major initiators involved in the development of atherosclerotic CVD are vascular production of reactive oxygen species (ROS) and lipid oxidation. In atherosclerosis development, ROS is associated with rapid loss of anti-inflammatory and anti-atherogenic activities of the endothelium-derived nitric oxide (NO(·)) resulting in endothelial dysfunction. In part involving activation of the transcription factor NF-κB, ROS have been involved in signaling cascades leading to vascular pro-inflammatory and pro-thrombotic gene expression. ROS is also a potent activator of matrix metalloproteinases (MMPs), which indicate plaque destabilization and rupture. The second initiator involved in atherosclerotic CVD is the oxidation of low-density lipoproteins (LDL). Oxidation of LDL in vessel wall leads to an inflammatory cascade that activates atherogenic pathway leading to foam cell formation. The accumulation of foam cells leads to fatty streak formation, which is the earliest visible atherosclerotic lesion. In contrast, the cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and hepatic apolipoprotein E (apoE) expression can improve cardiovascular function. SERCA2a regulates the cardiac contractile function by lowering cytoplasmic calcium levels during relaxation, and affecting NO(·) action in vascular cells, while apoE is a critical ligand in the plasma clearance of triglyceride- and cholesterol-rich lipoproteins.

Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis

Abstract: Lipoprotein(a) [Lp(a)], comprised of apolipoprotein(a) [apo(a)] and a low-density lipoprotein-like particle, is a genetically determined, causal risk factor for cardiovascular disease and calcific aortic valve stenosis. Lp(a) is the major plasma lipoprotein carrier of oxidized phospholipids, is pro-inflammatory, inhibits plasminogen activation, and promotes smooth muscle cell proliferation, as defined mostly through in vitro studies. Although Lp(a) is not expressed in commonly studied laboratory animals, mouse and rabbit models transgenic for Lp(a) and apo(a) have been developed to address their pathogenicity in vivo. These models have provided significant insights into the pathophysiology of Lp(a), particularly in understanding the mechanisms of Lp(a) in mediating atherosclerosis. Studies in Lp(a)-transgenic mouse models have demonstrated that apo(a) is retained in atheromas and suggest that it promotes fatty streak formation. Furthermore, rabbit models have shown that Lp(a) promotes atherosclerosis and vascular calcification. However, many of these models have limitations. Mouse models need to be transgenic for both apo(a) and human apolipoprotein B-100 since apo(a) does not covalently associated with mouse apoB to form Lp(a). In established mouse and rabbit models of atherosclerosis, Lp(a) levels are low, generally < 20 mg/dL, which is considered to be within the normal range in humans. Furthermore, only one apo(a) isoform can be expressed in a given model whereas over 40 isoforms exist in humans. Mouse models should also ideally be studied in an LDL receptor negative background for atherosclerosis studies, as mice don't develop sufficiently elevated plasma cholesterol to study atherosclerosis in detail. With recent data that cardiovascular disease and calcific aortic valve stenosis is causally mediated by the LPA gene, development of optimized Lp(a)-transgenic animal models will provide an opportunity to further understand the mechanistic role of Lp(a) in atherosclerosis and aortic stenosis and provide a platform to test novel therapies for cardiovascular disease.

Vascular Pathobiology: Atherosclerosis and Large Vessel Disease

Abstract: Large vessel arterial disease may be regarded as atherosclerotic or nonatherosclerotic; the latter includes less common diseases related to known genetic abnormalities, degenerative conditions, and specific immune and infectious processes. Atherosclerosis is a chronic vascular disease initially involving the intima of elastic and larger muscular arteries and characterized by the presence of fibroinflammatory lipid plaques (atheromas). It is a leading cause of morbidity and mortality in North America and results in major economic and health burden across the globe. Atherogenesis is a function of the interplay between an individual's genetic disposition, environmental exposure, and living habits adopted by the individual. The pathogenesis is complex, multifactorial and the relative importance of specific genetic and external factors vary among individuals. Growth of a plaque is a chronic dynamic inflammatory process involving innate and adaptive immunity with superimposed acute events. The most serious acute events are plaque rupture and atherosclerotic aneurysm rupture. Interactions between cells and matrix of the artery and serum constituents, leukocytes, platelets, and physical forces regulate the formation and growth of the fibroinflammatory lipid plaque. Regulation of gene expression in the plaque occurs through the DNA sequence and by miRNAs and other epigenetic processes that regulate translation and posttranslational events. There are dynamic molecular interactions in the microenvironment of the plaque among gene products that participate in inflammation, lipid metabolism, extracellular matrix remodeling, and thrombosis. Both local biological events at the blood-endothelial interface and systemic factors are involved. Thrombosis is associated with plaque growth, lumen occlusion, and plaque rupture. Focal plaque growth leads to the development of luminal stenosis, complicated plaques, and weakening of some vessel walls. Complicated plaques may become destabilized and lead to plaque rupture and occlusive thrombosis. Organs with atherosclerosis in the supply arteries develop clinical disease, including ischemic heart disease, stroke, and peripheral vascular disease. Known environmental and genetic risk factors are associated with increased disease. Risk reduction through risk stratification and treatment is a successful approach to prevention and to treatment of atherosclerosis.

Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor-I

Abstract: The role of endocrine IGF-I for atherosclerosis is unclear. We determined the importance of circulating, liver-derived IGF-I for fatty streak formation in mice. Mice with adult, liver-specific IGF-I inactivation (LI-IGF-I−/− mice, serum IGF-I reduced by approximately 80 %) and control mice received an atherogenic (modified Paigen) diet between 6 and 12 months of age. At study end, Oil Red O staining of aortic root cryosections showed increased fatty streak area and lipid deposition in female but not in male LI-IGF-I−/− mice compared to controls. Mac-2 staining of aortic root and measurements of CD68 mRNA level in femoral artery revealed increased macrophage accumulation in proportion to the increased fatty streak area in female LI-IGF-I−/− mice. Moreover, female LI-IGF-I−/− mice displayed increased serum cholesterol and interleukin-6 as well as increased vascular cell-adhesion molecule 1 (VCAM1) mRNA levels in the femoral artery and elevated VCAM1 protein expression in the aortic root. Thus, increased diet-induced fatty streak formation in female LI-IGF-I−/− mice was associated with increased serum cholesterol and signs of systemic inflammation, endothelial activation, lipid deposition, and macrophage infiltration in the vascular wall.

Perilla Oil Reduces Fatty Streak Formation at Aortic Sinus via Attenuation of Plasma Lipids and Regulation of Nitric Oxide Synthase in ApoE KO Mice

Abstract: Consumption of n-3 polyunsaturated fatty acids (PUFA) is associated with a reduced incidence of atherosclerosis. Perilla oil (PO) is a vegetable oil rich in α-linolenic acid (ALA), an n-3 PUFA. In this study, antiatherogenic effects and related mechanisms of PO were investigated in atherosclerotic mice. Apolipoprotein E knockout (ApoE KO) mice (male, n = 27) were fed high-cholesterol and high-fat diets containing 10 % w/w lard (LD), PO, or sunflower oil (SO) for 10 weeks. Plasma triglyceride, total cholesterol, and low-density lipoprotein cholesterol concentrations reduced in the PO and SO groups compared to the concentrations in the LD group (P < 0.05). The PO group showed reduced fatty streak lesion size at the aortic sinus (P < 0.05) compared to the sizes in the LD and SO groups. A morphometric analysis showed enhancement of endothelial nitric oxide synthase expression and reduction of inducible nitric oxide synthase expression in the PO group compared to that in the LD group (P < 0.05). Furthermore, aortic protein expression of intercellular cell adhesion molecule 1 and vascular cell adhesion molecule 1 was diminished in the PO group compared to that in the LD and SO groups (P < 0.05). These findings suggested that PO inhibited the development of aortic atherosclerosis by improving the plasma lipid profile, regulating nitric oxide synthase, and suppressing the vascular inflammatory response in the aorta of ApoE KO mice.

Attenuation of Atherosclerosis by 3,4-Dihydroxy- Hydrocinnamic Acid in Rabbits by Partial Inhibition of ACAT

Abstract: Polyphenols have been reported to have beneficial effects on cardiovascular disease. A polyphenolic compound, 3,4-dihydroxy-hydrocinnamic acid (3,4-DHHCA), has been shown to have antioxidative and antitumorigenic activities. However, the effect of 3,4-DHHCA on atherosclerosis is still unknown. Herein, we investigated the effects of 3,4-DHHCA on atherosclerosis in New Zealand White rabbits. Broad and fused fatty streak lesions were found in rabbits fed with high-cholesterol diet for 8 weeks. Administration of 3,4-DHHCA reduced atherosclerotic lesion formation and lesional accumulation of macrophage in rabbits fed with cholesterol diet without systemic or local toxicity. Hepatic acyl-coenzyme A: cholesterol acyltransferase (ACAT) activity was decreased after treatment with 3,4-DHHCA by 22% in cholesterol diet-fed rabbits compared with the control group. These results indicate that 3,4-DHHCA had antiatherogenic effects in rabbits, possibly by partial inhibition of ACAT.

(atherosclerosis/autoantibodies to oxidized low density lipoprotein/malondialdehyde/4-hydroxynonenal)

Abstract: It has been proposed that low density lipo- protein (LDL) must undergo oxidative modification before it can give rise to foam cells, the key component of the fatty streak lesion of atherosclerosis. Oxidation of LDL probably generates a broad spectrum of conjugates between fragments of oxidized fatty acids and apolipoprotein B. We now present three mu- tually supportive lines of evidence for oxidation of LDL in vivo: (i) Antibodies against oxidized LDL, malondialdehyde-lysine, or 4-hydroxynonenal-lysine recognize materials in the athero- sclerotic lesions of LDL receptor-deficient rabbits; (ii) LDL gently extracted from lesions of these rabbits is recognized by an antiserum against malondialdehyde-conjugated LDL; (iii) autoantibodies against malondialdehyde-LDL (titers from 512 to >4096) can be demonstrated in rabbit and human sera.