Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. When severe, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected.
The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:
Platelet-activating factor, also known as PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation and degranulation, inflammation, and anaphylaxis. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.
The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.
Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.
Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.
Apolipoprotein C-IV, also known as apolipoprotein C4, is a protein that in humans is encoded by the APOC4 gene.
Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP is a protein that in humans is encoded by the SCAP gene.
Platelet-activating factor acetylhydrolase IB subunit alpha is an enzyme that in humans is encoded by the PAFAH1B1 gene. The protein is often referred to as Lis1 and plays an important role in regulating the motor protein Dynein.
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Oxidized low-density lipoprotein receptor 1 also known as lectin-type oxidized LDL receptor 1 (LOX-1) is a protein that in humans is encoded by the OLR1 gene.
Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitously expressed in many tissues, sortilin is most abundant in the central nervous system. At the cellular level, sortilin functions in protein transport between the Golgi apparatus, endosome, lysosome, and plasma membrane, leading to its involvement in multiple biological processes such as glucose and lipid metabolism as well as neural development and cell death. Moreover, the function and role of sortilin is now emerging in several major human diseases such as hypertension, atherosclerosis, coronary artery disease, Alzheimer’s disease, and cancer. The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease.
Platelet-activating factor acetylhydrolase 2, cytoplasmic is an enzyme that in humans is encoded by the PAFAH2 gene. It is one of several PAF acetylhydrolases.
Darapladib is an inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) that is in development as a drug for treatment of atherosclerosis.
The chronic endothelial injury hypothesis is one of two major mechanisms postulated to explain the underlying cause of atherosclerosis and coronary heart disease (CHD), the other being the lipid hypothesis. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol (LDL-C) in the pathogenesis of atherosclerosis, the two hypotheses have become tightly linked by a number of molecular and cellular processes.
Lysophosphatidylcholines, also called lysolecithins, are a class of chemical compounds which are derived from phosphatidylcholines.
Varespladib is an inhibitor of the IIa, V, and X isoforms of secretory phospholipase A2 (sPLA2). The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation. From 2006 to 2012, varespladib was under active investigation by Anthera Pharmaceuticals as a potential therapy for several inflammatory diseases, including acute coronary syndrome and acute chest syndrome. The trial was halted in March 2012 due to inadequate efficacy. The selective sPLA2 inhibitor varespladib (IC50 value 0.009 μM in chromogenic assay, mole fraction 7.3X10-6) was studied in the VISTA-16 randomized clinical trial (clinicaltrials.gov Identifier: NCT01130246) and the results were published in 2014. The sPLA2 inhibition by varespladib in this setting seemed to be potentially harmful, and thus not a useful strategy for reducing adverse cardiovascular outcomes from acute coronary syndrome. Since 2016, scientific research has focused on the use of Varespladib as an inhibitor of snake venom toxins using various types of in vitro and in vivo models. Varespladib showed a significant inhibitory effect to snake venom PLA2 which makes it a potential first-line drug candidate in snakebite envenomation therapy. In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.
Remnant cholesterol, also known as remnant lipoprotein, is a very atherogenic lipoprotein composed primarily of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). Stated another way, remnant cholesterol is all plasma cholesterol that is not LDL cholesterol or HDL cholesterol, which are triglyceride-poor lipoproteins. However, remnant cholesterol is primarily chylomicron and VLDL, and each remnant particle contains about 40 times more cholesterol than LDL.
Sally Priscilla Anna McCormick is a New Zealand biochemistry academic. She is currently a full professor at the University of Otago.
