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The Beneficial Effect of Omega-3 PUFA and L-Arginine on Endothelial Nitric Oxide (NO) Bioavailability
Published in Robert Fried, Richard M. Carlton, Flaxseed, 2023
Robert Fried, Richard M. Carlton
Endothelial NO also controls the expression of genes involved in atherogenesis. NO decreases the expression of chemoattractant protein MCP-1 and of a number of surface adhesion molecules, thereby preventing leucocyte adhesion to vascular endothelium and leucocyte migration into the vascular wall. This offers protection against early phases of atherogenesis. Also, the decreased endothelial permeability, the reduced influx of lipoproteins into the vascular wall and the inhibition of low-density lipoprotein oxidation may contribute to the anti-atherogenic properties of endothelial NOS-derived NO.
Features of Lipid Metabolism in Diabetes Mellitus and Ischemic Heart Disease
Published in E.I. Sokolov, Obesity and Diabetes Mellitus, 2020
Clinicians and morphologists proved in numerous investigations that the main role in atherogenesis is played by the reaction of lipoproteins with the smooth muscle cells of an arterial wall. It is cholesterol (unesterified) that affects the macromolecular structure, permeability, and electrical potential of a membrane. Great importance in the development of atherosclerosis of the coronary vessels is attached to activation of the peroxide oxidation of lipids in the cells and tissues of an organism that occurs in the development of DM. The key link in disturbance of the peroxide oxidation of lipids in IHD and DM patients is the “lipid triad” that integrates a combination of functioning of carbohydrate and lipid metabolism. The disturbance of various relations (biochemical) in the lipid triad causes lesion of the cardiac myocyte membranes because of potentiation of the catecholamines and activation of lipases and phospholipases.
Atherosclerosis, Arteriolosclerosis and Vasculitis
Published in Jeremy R. Jass, Understanding Pathology, 2020
Epidemiological studies have shown that the major risk factors of atherosclerosis are diet (i.e. one high in cholesterol), hyperlipidemia of genetic origin, hypertension, smoking and diabetes mellitus. Other risk factors include male gender, obesity, age and physical inactivity. In the past, two main theories were put forward to explain the growth of an atheromatous plaque. The first envisaged the insudation of cholesterol from the bloodstream into the intima, this in turn stimulating the proliferation of smooth muscle cells. The second theory focused on the progressive laying down and organisation of platelet thrombi. The contemporary view combines elements of both theories but views atherosclerosis as an inflammatory response to intimal injury (Ross & Fuster, 1996). The suggested steps are shown in Figure 25. Thrombosis is now viewed as a late complication of atheroma, rather than as a predisposing event. The sequence of events outlined in Figure 25 fits with the risk posed by hypercholesterolemia and the direct damaging influence of hypertension and cigarette smoke upon endothelial cells. Considerable research is under way to map the molecular steps involved in the above pathway, with the aim of developing therapeutic strategies to block the process of atherogenesis. However, a healthy diet, regular exercise and avoidance of tobacco would be a useful start to preventing this disease. Lifestyle improvements such as these are already having a beneficial effect in the West.
Anti-inflammatory strategies for atherosclerotic artery disease
Published in Expert Opinion on Drug Safety, 2022
Federica Agnello, Davide Capodanno
Several mediators of atherogenesis have been targeted by novel anti-inflammatory drugswith no convicing demonstration of clinical benefit so far. Darapladib is a selective inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), which has been specifically developed for the treatment of atherosclerosis. Preclinical and clinical tests of this drug produced conflicting results. Indeed, the inhibition of this enzyme, which is known to generate inflammatory mediators [93,94], produced promising result in diabetic and hypercholesterolemic swines, reducing the development of advanced coronary atherosclerosis, but showed no clinical benefit in two large phase 3 trials in humans, namely the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, recruiting stable CAD patients, and the SOLID-TIMI 52 (Stabilization Of pLaques usIng Darapladib-Thrombolysis In Myocardial Infarction 52), recruiting ACS patients [93–97]. Some authors speculate about the possibility of beneficial effects from this treatment only in subjects with higher baseline levels of Lp-PLA2. However, the available evidence suggests that the Lp-PLA2 activity could predict cardiovascular events only in individuals with stable CAD, advocating a role as inflammation biomarker without a causal role; furthermore, loss-of-function mutations of gene encoding for Lp-PLA2 do not support a cardiovascular protective effect [98].
Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis
Published in Toxicology Mechanisms and Methods, 2021
Liping Jiang, Songsong Luo, Tianming Qiu, Qiannan Li, Chunteng Jiang, Xiance Sun, Guang Yang, Cong Zhang, Xiaofang Liu, Lijie Jiang
Atherosclerosis, which is a chronic inflammatory disease, is the leading cause of mortality worldwide (Soehnlein and Libby 2021; Xu et al. 2021). Early stages of atherogenesis characteristics are endothelial cell dysfunction, persistent inflammatory response, and changed vascular homeostasis (Mehta and Malik 2006; Badimón et al. 2009). Arterial inflammation is triggered by endothelium, ultimately results in endothelial cell activation and recruited inflammatory cells to the blood vessels (Mudau et al. 2012). Genetic, lifestyle, and environmental factors would all contribute to the occurrence of arteriosclerotic vascular disease. Epidemiological studies have shown evidence of the link between cigarette smoke and atherosclerosis (Barnoya and Glantz 2005; Raghuveer et al. 2016; Arnett et al. 2019). However, the mechanism of tobacco smoke-induced atherosclerosis remains unclear.
Inflammasomes: a preclinical assessment of targeting in atherosclerosis
Published in Expert Opinion on Therapeutic Targets, 2020
Jeremiah Stitham, Astrid Rodriguez-Velez, Xiangyu Zhang, Se-Jin Jeong, Babak Razani
Atherosclerosis has long been recognized as the driving force behind cardiovascular disease (CVD), which remains the leading cause of death in the United States [1]. Furthermore, despite increased use of cardio-preventive medications (i.e. potent lipid-lowering drugs and anti-platelet agents), the once high rate of decline in CVD mortality has now slowed [2,3]. This alarming deceleration, in combination with high disease burden and associated cost, has highlighted the need for novel therapeutics aimed at reversing atherogenesis. Atherosclerosis is the result of lipid accumulation and chronic inflammation within the arterial vasculature [4]. These two processes are linked via the NLRP3 inflammasome, which is predominantly expressed in macrophages and lipid-laden foam cells, neutrophils, as well as endothelial cells (ECs) residing within areas of vascular inflammation and atherosclerotic plaque formation [5,6]. NLRP3 inflammasome activation has been proposed to be a critical catalyst for atherogenesis facilitating the production and maturation of pro-inflammatory cytokines, such as interleukin‐1β (IL-1β) and interleukin‐18 (IL-18), both of which are major contributors to atherosclerosis [4,7,8].