Q: Why does LDL cause heart attacks? A: because... Q: What is the offending agent in coronary heart disease? A: Low Density Lipoprotein (LDL) Q: How do the "Cholesterol Quartet" disorders elevate plasma LDL? A: They impair the activity of hepatic LDL receptors (LDLRs). Q: How are LDL's removed from (circulation) the plasma? A: When apoB-100 binds to LDLRs, LDL is endocytosed in coated pits. Q: How does the cell liberate cholesterol from internalized LDLs? A: Degradation in lysosomes. Q: How are LDLR's controlled? A: Negative feedback regulation - when cholesterol in hepatocytes rises, LDLR gene transcription is suppressed Q: When is LDLR gene transcription induced? A: when hepatic cholesterol levels fall - with more LDLRs, LDL is taken up more quickly. Q: What do statins do? A: LDL lowering properties - in mitochondria you prevent HMG CoA from going to cholesterol by blocking HMG CoA reductase. Q: What controls hepatic pools of cholesterol? A: two ABC transporters - ABCG5 and ABCG8 Q: how do ABCG5 and ABCG8 function? A: In the intestine they re-excrete cholesterol into the gut lumen/in hepatocytes they secrete cholesterol into the bile. Q: What accounts for 5% of heart attacks in patients over 60? A: Familial hypercholesterolemia (FH) - one of the cholesterol quartet Q: What do all four of the disorders in the Cholesterol Quartet have in common? A: Each of their defects elevates LDL by decreasing LDLR activity in the liver. Q: What is responsible for 50% of all mortality in the USA, Europe and Japan? A: Atherosclerosis - the principle cause of heart attack, stroke and gangrene. Q: In atherosclerosis why do the lesions form? A: Insult to the arterial endothelium and smooth muscle results in an excessive, inflammatory-fibroproliferative response. Q: What is the normal response to arterial insult A: a protective formation of fibrofatty and fibrous lesions, accompanied by inflammation. Q: What is the "fatty streak?" A: The earliest recognizable lesion of atherosclerosis. Q: What are fatty streaks in atherosclerosis? A: An aggregation of lipid-rich macrophages within the innermost layer of the arterial wall. Q: What follows fatty streaks in the progression of atherosclerosis? A: Intermediate lesions Q: What are intermediate lesions in atherosclerosis? A: layers of macrophages and smooth muscle cells Q: What follows intermediate lesions in the progression of atherosclerosis? A: occlusive lesions called fibrous plaques - these project into the lumen of the BVs Q: What causes most of the sudden deaths from myocardial infarcts? A: Ruptures or fissures of the fibrous plaques (fibrous cap), resulting in hemorrhage into the plaque, thrombosis and occlusion. Q: vascular endothelium is a dynamic organ. What does it control? A: this layer locally controls vascular tone and permeability, as well as the defensive processes (thrombosis and inflammation) Q: how does the endothelium control vasodilatation and constriction A: the production of nitrous oxide from arginine using nitrous oxide synthase (NOS) Q: NO is secreted continuously in the resting state. How does NO act on vascular smooth muscle cells? A: Increase in guanylate cyclase--leads to decreased intracellular calcium and thus smooth muscle relaxation. Q: What other physiological benefits does NO have? A: Reducing platelet adhesion and aggregation, reducing leukocyte adhesion and controlling vascular growth. Q: Fundamental role of endothelium in blood flow? A: Maintenance of antithrombotic surface. Q: Fatty streaks are formed by what series of events? A: Arterial insult - trapping of lipoprotein - glycoprotein adhesions - monocyte attachment and migration - monocytes to macrophages - lipid accumulation. Q: What three processes result in atherosclerotic lesions? A: Proliferation of smooth m cells/macrophages - increase in smooth m in CT matrix - accumulation of lipid and cholesterol in CT matrix Q: What is the difference between normal physiological insults and an atherosclerotic causing insult? A: Respectively: short lived insult and rapid repair/healing, versus chronic insult that doesn't let up. Q: What promotes cell recruitment and proliferation in atherogenesis? A: NO, cytokines and growth factors. Q: What characterizes the advanced stages of atherosclerosis? A: Thick plaques, vascularized plaques, fissuring/cracking, blah blah leading to formation of thrombosis. Q: How does oxLDL play a role in endothelial injury? A: OxLDL may diretly injure the endothelium and play an initial role in the increased adherence and migration of moncytes and T lymphocytes. Q: How do foam cells form? A: Once monocytes and lymphocytes enter the intima of the artery, uptake of oxLDL by the macrophages leads to foam cell foration. Q: are LDLs susceptible to oxidative modification, and what would potentiate this process? A: YES!!! Small, dense LDL are particularyl sensitive to ox. modification and many factors such as cigarette smoke, insulin resistence, diabetes, will potentiate it. Q: T or F Once oxLDL gets trapped in the arterial wall, it is 'protected' from causing furter damage? A: FALSE. OxLDL in the arterial wall leads to increased oxidant stress (-O2 and -OH) via the enzymatic actions of NADP/NADPH, NOS, and xanthine oxidase. The excess of free radicles amplifies the impariment of NO, cell permeability, endocytic activity and Q: What effects does oxLDL have on platelets and blood clotting? A: oxLDL promotes aggregation and coagulation. Note: NO derived from the endothlium and platelets is a powerful inhibitor of platelet adhesion and aggregation. OxLDL reduces NO activity thus promoting thrombin generationa nd platelet aggregation. Q: How does oxLDL attribute to the formation of acute coronary syndromes? A: OxLDL effects platelets promoting aggregation and coagulation. OxLDL also reduces NO activity which promotes both thrombin generation and platelet aggregation. oxLDL also alters the balance to prostacyclin and endothelin to increase aggreation. Q: What do 'scavenger' receptors bind to and what cells are they on? A: Scavenger receptors are on phagocytic macrophages. They are nonspecific receptors that bind various types of molecules including modified LDL particles. Q: What is a unique property of scavenger receptors compared to LDL receptors and what does this allow cells to do? A: Scavenger receptors are not subject to downregulation allowing their continued presence to take up oxLDLs long after intracellular cholesterol levels are elevated. Q: What is a foam cell and detection of foam cells is initally evidence of what? A: Foam cells are macrophages that are engorged with lipids. Accumulation of foam cells in subendothelial space is the first evidence of developing atherosclerotic plaque called fatty steak. Q: What role do macrophages play in atherogenesis and how do they cause this? A: Normally macrophages act as scavenger cells in addition to their antigen-presenting activity. They internalize oxLDL through scavenger and putative oxLDL receptors and also oxidize LDL through various pathways (eg. lipoxygenase). OxLDL plays a role in Q: What vitamines or drugs are used to prevent and reduce lesions of atheroscelerosis? A: antioxidant probucol, vit E, vit C, and possibly beta-carotene. Q: What are the two isoenzyes of nitric oxide synthetase and where are they expressed? A: eNOS: constitutively expressed in the endothelium. iNOS: inducible, found in vascular smooth muscle and macrophages. Q: What does NO do and how does it do it? A: NO causes vasodilation via stimulation of guanylate cyclase and cGMP production. Q: T or F Low levels of NO contributes of developing High BP? A: T. Current data shows that this may be the case. Q: NO may be important protection against atherosclerosis, how does it do this? A: NO reduces monocyte adhesion to the endotheilum and proliferation of vascular smooth muscle cells. Q: PPAR-gamma has antiflamatory properties, what does it do to give these properites? A: it is up-regulated in activated macrophages and 1)inhibits the secretion of iNOS 2) inhibits gelatinase B which is involved in tissue damage 3)and it inhibits a scavenger receptor A which would usually play a role in cell adhesion and uptake of oxLDL. Q: PPAR-gamma has both protective and undesirable effects. What is the basis of each one? A: Protective: reduced secretion of human atheroma monocyte/macrophage cells of atrix metalloproteinase-9 (this enzyme is implicated in plaque rupture. Negative: PPAR-gamma is activated by oxLDL's and is expressed at high levels in the foam cells of atherosc Q: What is the focus of new drugs for treating atherosclerosis? A: contol LDL levels and LDL oxidation. Q: Statins control LDL levels but they are expensive, there is an alternative drug class. What is their function? A: There is inhibitors of enzymes required for lipoprotein s ynthesis and metaboism. (eg. MTP inhibitors, and enzymes used in LDL oxidaiton.) Q: PPAR-alpha regulates several aspects of fatty acid metabolis, including berta oxidation and uptake of fatty acids form triglyceride-rich lipoproteins. How does PPAR-alpha raises HDL levels A: It stimulates expression of apoA-1 Q: What does PPAR-gamma do? A: it regulates fat cell development and glucose homeostasis and is the molecular target of the TZD (thiazolidinedione) class of insulin sensitizers used in treating type 2 diabetes. It has also reasently been shown t increas ABC A1 expression and cholester