Atherosclerosis

Jana Novotn

Atherosclerosis

Disease of cardiovascular system affecting vessel wall. It leads to the narrowing of arteries or complete blockage. Its main components are endothelial disfunction, lipid deposition, inflammatory reaction in the vascular wall. Remodeling of vessel wall.

Atherosclerosis

Intense cross-talk between EC, VSMC, plasma-derived inflammatory cells, lymphocytes (involves array of chemokines, cytokines, growth factors). Attraction of cells to the sites of atherosclerotic lesion. Migration, proliferation, apoptosis, excess production of extracellular matrix.

Arterial wall

Normally arterial endothelium repels cells and inhibits blood clotting.

The lumen of healthy arterial wall is lined by confluent layer of endothelial cells.

Arterial wall
1. 2.

3.

Three layers: Intima (subendothelial layer) Media (middle layer) with smooth muscle cells (VSMC) Adventitia (outer layer) with connective tissue and nerves

Arterial wall

Endothelium controls important function: 1. the ability of blood vessels to dilatate (vasodilatation) 2. the ability of blood vessels to constrict (vasoconstriction) Endothelium regulates tissue and organ blood flow.

Arterial wall

Endothelium releases variety substances to control vasomotor tone:

Exercise is an important mechanical stimulus mediated by shear stress to increased blood flow. Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall. The flow-dependent dilatation of pre-capillary resistance as well as conductance allows blood flow to increase according metabolic demands.

prostacyclines hyperpolarizing factor endothelin NO

Arterial wall

In the case of intact endothelium, the stimulus for vasodilatation:

mechanical stimulation by blood flow catecholamines, bradykinin, platelets-released serotonin stimulate specific receptors direct vasoconstrictor action of the stimuli on the VSMC outweighs the endothelium-dependent vasodilatator effect this action leads to paradoxial vasoconstriction

In the case of endothelium disfunction:

(Hypercholesterolemia and other cardiovascular risk factors are associated with endothelial disfunction).

Nitric oxide (NO)

Factor which controls vasodilatation: endotheliumderived relaxing factor (EDRF)

Arginine
O2 + NADPH

NO + citrulline
NADP+

The activity of eNOS is controlled by intracellular Ca2+. eNOS endothelial constitutive enzyme (continually expressed) and iNOS inducible, from VSMC. NO cause vasodilatation via stimulation guanylate cyclase and cGMP production.

The development of atherosclerosis

The key event damage to the endothelium caused by excess of lipoproteins, hypertension, diabetes, components of cigarette smoke. Endothelium becomes more permeable to lipoproteins. Lipoproteins move below the endothelial layer (to intima). Endothelium loses its cell-repelent quality. Inflammatory cells move itno the vascular wall.

The scheme of LDL a HDL

Triggers for inflammation in atherosclerosis

LDL retained in the intima (in part by binding to proteoglycan) undergoes oxidative modification. Lipid hydroperoxides, lysophospholipides, carbonyl compounds localize in the lipid fraction. Oxygen free-radicals inactivate NO rapidly. NO + superoxide (O2.-) peroxynitrite (ONOO-). NO has no longer vasoprotective function.

The development of atherosclerosis

Disfunctional endothelium express adhesion molecules selectins, mediated the rolling interaction of cells. The key molecule - vascular cell addhesion molecule-1 (VCAM-1) promotes monocytes adhesion (precursors of macrophages). Addhering cells are stimulated by monocyte chemoattractant protein-1 (MCP-1). Monocytes cross the endothelium, settle down in the intima.

NO inactivation due to oxidative stress

Xanthin oxidase and NADH/NADPH oxidase produces of O2.- in macrophages after stimulation with angiotensin II (a key mediator of oxidative stress in vascular wall). In the early stage of process, ROS are released from endothelium. In the later atherogenetic process, ROS are produced by macrophages in thickening vessel wall.

Schchinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055

Triggers for inflammation in atherosclerosis

Reduced NO bioactivity, increased oxidative stress leads to tyrosine nitration of protein in vessel wall. Nitrotyrosine and oxidized LDL activate transkriptional factor NF-kB (nuclear factor kappa-lightchain-enhancer of activated B cells). NF-kB increases proliferation of VSMC Reduced NO bioactivity and enhanced oxidative stress stimulate cytokine production (interleukins, TNFa, MCP-1, interferons) and monocytes attraction.

Inflammation in atherosclerosis (mononuclear cells)

Endothelial cells undergo inflammatory activation, produce different leukocyte adhesion molecules (VCAM-1). Monocytes penetrate into tunica intima. Their receptor CCR2 interact with MCP-1
Resident monocytes acquire characteristics of tissue macrophages. Macrophages express scavenger receptors for oxidized LDL, internalized lipoprotein particles. Macrophages change to foam cells (lipid droplets are accumulated within the cytoplasm). Foam cells secrete proinflammatory cytokines. This process amplify local inflammation and ROS.
Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874

Inflammation in atherosclerosis (T-lymhocytes)

T-lymphocytes enter the intima facilitated by VCAM-1 and trio chemokines- IP-10 (inducible protein-1), Mig (monokine induced by interferon-g) and I-TAC (interferon-inducible T-cells achemoattractant). Trio chemokines bind to CXCR3 chemokine receptor expressed by T-cells in the atherogenic lesion.
T-cells are activated by antigens (Ox-LDL, heatshock proteins), produce cytokines. Cytokines influence behaviour of other cells present in the atheroma. CD154 (protein expressed on activated T-cells) binding to CD40 ligand expressed on macrophages induces the epression of other cytokines, MMPs, tissue factor.
Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874

Inflammation in atherosclerosis (mast cells)

Mast cells infiltrate to the intima. Chemoattractant eotaxin mediate migration of mast cells and interacts with the chemokine receptor CCR3. Resident mast cells in the intima degranulate, release TNF-a, heparin, and enzymes activating proMMPs.

Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874

The process of atherogenesis an overview

The process of atherogenesis

Lipid entry into the arterial wall is a key process in atherogenesis. Hypercholesterolemia factor for VCAM-1 and MCP-1 induction. LDL and VLDL are most atherogenic, enter vascular wall more easily. LDL in plasma are protected against oxidation by vit. E, ubiquinon, plasma antioxidants (b-carotene, vit. C). Out of plasma, LDL phospholipides and fatty acids oxidize.

The process of atherogenesis

Activated macrophages produce enzymes lipoxygenases, myeloperoxidase, NADPH oxidase ROS Oxidized LDL are cytotoxic to endothelial cells, mitogenic for macrophages. Oxidized LDL apolipoprotein apoB100 bind to the scavenger receptor. Scavenger receptors are not subjected to regulation by intracellular cholesterol level. Macrophages take up oxidized LDL, overload with lipids.

The process of atherogenesis

Foam cells ruptured (apoptosis). Lipid release to intima and their acumulation becomes centre of atherosclerotic plaques.

The lipid center and fibrous cap are the main parts of a mature atherosclerotic plaque. Plaque emerges from the structurally changed vascular wall. So-called vulnerable plaque ruptures easily. The thrombus formed at the rupture site.

The process of atherogenesis

Plaque growth periodically accelerated by a cycle of plaque rupture and thrombosis. This happens:

Active macrophages and T lymphocytes preferentially reside at the edge of the plaque. Macrophages secrete enzymes degrade extracellular matrix of the cap (MMP collagenases, gelatinases, and stromelysin) T-cells activated by macrophages secrete IFN-g and pro-inflammatory cytokines IL-1, IL-2, and TNF-a.

The process of atherogenesis

The process of atherogenesis

IFN-g induces macrophage MMP expression. IFN-g inhibits VSMC proliferation and collagen synthesis which further weakening the cap. VSMC undergo apoptosis. After plaque rupture the area is exposed its interior to the blood. The interior of the plaque is highly thrombogenic the smallmolecular-weight glycoprotein (tissue factor) initiates the extrinsic clotting cascade. Tissue factor complexes with factor VII/VIIa, factor IX and X are activated. Platelets are activated and thrombus forms quickly on the surface of a ruptured plaque. Thrombus completely occludes the arterial lumen. It cause tissue necrosis (myocardial infarction or brain stroke).

Cardiovascular risk and its assesment

Plasma concentration of lipoproteins (LDL-cholesterol, HDL-cholesterol, and triacylglycerols) 5.2 mmol/L (200 mg/dL) increases the risk. Optimal level of LDL-cholesterol - 2.6 mmol/L (100 mg/dL)

Cardiovascular risk and its assesment

The risk of atherosclerotic event can be decreased by:

Cholesterol low diet Exercise Smoking cessation Control of high pressure Drugs statins, fibrates (fibric acid), ezetimibe, antioxidants

Statins inhibit intracellular cholesterol synthase (HMG-CoA reductase). Fibrates - lower plasma cholesterol by stimulating LPL, decreasing TAG concentration, and increasing HDL. Ezetimibe inhibitor of intestinal cholesterol transporter. b-carotene, a-tocoferol, vitamin C (such as these contained in fruits or their combinations) have preventive benefit, protect LDL against oxidation.

Schchinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055