Atherosclerosis Flashcards

Question

macrophages and collagen/ fibrous cap

Answer 1

• Matrix metalloproteases • MMP-1 • MMP-2 • MMP-9 • MMP-14 • MMP-1, MMP-2, MMP-9 cleave collagen • Inhibited by TIMPs • TIMP-1 overexpression reduces atherosclerotic tissue weakening • Catalytic site contains Zn • Activate each other by proteolysis • MT-MMPs are transmembrane proteins that activate other MMPs Evidence for role of MMPs: • It is possible to delete single genes from mice to examine their function in disease in vivo (knockout mice) • Atherosclerosis-prone mouse Ldlr and Apoe models have more collagen in plaques (stronger and less rupture-prone) if also knockout for: • Mmp14 • Mmp13 • Mmp9 • Timp1 overexpressing mice – also more collagen in plaques (stronger and less rupture-prone)

Answer 2

1. macrophages in atherosclerotic plaques are from monocytes via endothelium 2. macrophages in atherosclerotic plaques lyse matrix via MMPs, secrete free radicals, oxidise LDL, are activated by oxidised LDL, phagocytose, release growth factors, express tissue factor and kill other cells 3. unstable atherosclerotic plaques are rupture-prone and contain increased macrophages

Answer 3

They have demonstrated that the extracellular matrix is actively destroyed by MMPs which are locally overexpressed by the macrophages.11 1. In the weakened plaque the number of macrophages producing MMP is increased and the number of smooth muscle cells repairing the extracellular matrix is decreased. 2. This imbalance between extracellular matrix synthesis and degradation is a solid basis for plaque rupture. 3. Activated T lymphocytes produce interferon (which decreases the synthesis of collagen I and III by smooth muscle cells12). 4. The T lymphocytes also influence the degradation of the ECM by stimulating macrophage production of MMP involving CD40 ligation.13 5. MMP expression is also induced by oxidised lipids contained in the lipid core. Oxidised LDL contributes to the plaque weakening by decreasing the natural inhibitor of MMP (TIMP-1) expressed by the macrophages, and by inducing apoptosis of the smooth muscle cells. 6. In contrast, high density lipoprotein (HDL) has a protective effect. Paraoxonase and lecithine–cholesterol acyltransferase (LCAT) are HDL associated enzymes; paraoxonase protects LDL and HDL from oxidation, and LCAT prevents the formation of oxidised lipids in LDL.

Answer 4

At the cellular level, the principal players are the endothelial cells, smooth muscle cells, macrophages, T lymphocytes, and neutrophils, and their mutual interactions will result in plaque rupture.

Answer 5

Endothelial cells play a pivotal role since they represent the major barrier against thrombosis, and their dysfunction results in attracting inflammatory cells (dysfunctional endothelial cells allow T lymphocyte recruitment via over-expression of the cell adhesion molecules) within the plaque where they can induce spasm, and participate in the thrombogenesis.

Answer 6

thick fibrous cap smaller lipid pools few inflammatory cells dense extracellular matrix ntact and thick fibrous cap that is made up of smooth muscle cells in a matrix rich in type I and III collagen.

Answer 7

lower LDL increase HDL Decrease Ang II, Oxidative stress, blood pressure

Answer 8

autopsy findings, where definitive proof does not exist because of a lack of prospective animal or human data confirming a cause-and-effect relationship

Answer 9

Clearly, fibrous cap thickness, necrotic core size, and positive remodeling are critical morphological features that distinguish TCFAs and ruptures from earlier progressive lesions, defined as pathological intimal thickening or fibroatheromas.

Answer 10

vulnerable plaques were commonly observed in patients dying a sudden coronary death and were more common in plaque ruptures than in stable plaques.27 The number of vulnerable plaques correlated with both high total cholesterol and the total cholesterol/high-density lipoprotein cholesterol ratio.27 In subjects dying of plaque rupture, additional lesion sites remote from the culprit plaque typically show TCFAs in 70% of cases. On the other hand, TCFAs are less frequent (30%) in cases where death is attributed to fibrocalcific plaques with flow-limiting stenosis, regardless of MI status, or plaque erosion

Answer 11

our inability to accurately detect vulnerable plaques in humans in vivo and because of the lack of an animal model. Therefore, a major limitation today exists partly because the precise mechanisms of progression from an asymptomatic stable to high-risk plaque (TCFA or vulnerable plaque) that lead to rupture and thrombosis are incompletely understood.

Answer 12

High importance of collagen synthesis and breakdown in the maintenance of the integrity of the fibrous cap. VSCMs synthesize essential ECM proteins (eg collagen and elastin). This process may be inhibited by interferon-γ (IFN-γ) secreted by activated T cells, thereby disrupting collagen synthesis. Importantly, the expression of CD40 ligand on T cells may promote tissue proteolysis through the release and activation of matrix-degrading enzymes produced by vascular smooth muscle cells and inflammatory macrophages. Activated macrophages within the fibrous cap can secrete tissue proteases that support the breakdown of collagen and elastin to peptides and amino acids. The loss of structural molecules provided by the extracellular matrix can thin and weaken the fibrous cap, rendering it particularly susceptible to rupture and acute coronary syndromes. Additional factors involved in the activation of macrophages include tumor necrosis factor-α (TNF-α), macrophage colony-stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1),among others

Answer 13

those lesions with intact fibrous caps of <65 μm observed at other (oftentimes multiple) sites in the coronary vasculature, in patients dying of acute plaque rupture, that are designated vulnerable plaques or TCFAs. Therefore, the current definition of vulnerability is exclusive to plaque rupture.

Answer 14

* Intraplaque hemorrhage directs an atheroprotective macrophage phenotype M-hem: antioxidative enzymes * Probably a generic response to hemorrhage • Novel ATF1-pathway, mediated by AMPK (ATF-1 is required for this protective response induced by heam) Physical binding of ATF1 to HO-1 and LXR genes induced by heme in blood-derived macrophages

Answer 15

Physical binding of ATF1 to HO-1 and LXR genes induced by heme in blood-derived macrophages * Novel ATF1-pathway (ATF-1 is required for this protective response induced by heam; Mediated by AMPK and reproduced by metformin ) * HO-1 antioxidant / anti-inflammatory * LXR – foam cell protection * Reciprocal storage of iron and lipid * LXR * Nuclear receptors for cholesterol overload * Activate cholesterol efflux to HDL * ATF1 * Closest homolog of CREB1 (which transcriptional effects of cAMP) * Survival factor

Atherosclerosis Flashcards

(39 cards)