Doc. Dr Zvezdana Kojić Decembar 2004.

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Biolo ški mehanizmi regulacija - Fiziologija kardiovaskularnog sistema -. Aterogeneza: značaj lipidskih poremećaja i oksidativnog stresa. Novi faktori rizika za ishemijsku bolest srca. Doc. Dr Zvezdana Kojić Decembar 2004. Atherosclerosis: a multifactorial disease. - PowerPoint PPT Presentation

Transcript of Doc. Dr Zvezdana Kojić Decembar 2004.

  • Aterogeneza: znaaj lipidskih poremeaja i oksidativnog stresa.

    Novi faktori rizika za ishemijsku bolest srca

    Doc. Dr Zvezdana KojiDecembar 2004.Bioloki mehanizmi regulacija- Fiziologija kardiovaskularnog sistema -

  • Atherosclerosis:a multifactorial disease

  • Arterial wall:structure and function

  • Different stages of atherosclerotic plaquedevelopment

  • Vascular endothelium modificationin atherosclerosis

  • Plaque formation1 Fatty streak

  • Plaque formation2 Fibrous cap

  • Plaque formation3 Lipid core

  • Lipid core constitutionActivated macrophages accumulate lipids

  • Lipid core constitutionLDL oxidation

  • Parietal vascular inflammationThe activated macrophage produces inflammatory cytokines

  • From plaque to thrombosis, key event: plaque rupture

  • Plaque vulnerabilityKey role of macrophages

  • Vulnerable plaqueKey role of the macrophage in vascular wall inflammation

  • Fibrinogen is an independent risk factorfor atherosclerosis

  • Vulnerable plaqueKey role of the macrophage in the degradation of the fibrous cap

  • Tissue factor: the initiator of coagulation and thrombogenesis in vivo

  • Tobacco and atherosclerosis

  • Dyslipidemia and atherosclerosis

  • Novi faktori rizikaADMA ?homocisteingrelin, leptinmokrana kiselinaMg++, Fe++, Zn++, Cu++

  • LiteraturaLi AS., Glass CK. PPAR and LXR-dependent pathways controlling lipid metabolism and development of atherosclerosis. J Lip Res., 2004, 45(12): 2161-73. Francois M, Kojda G. Effect of hypercholesterolemia and of oxidative stress on the nitric oxide-cGMP pathway. Neurochem Int. 2004 Nov;45(6):955-61. Bursill CA, Choudhury RP, Ali Z, Greaves DR, Channon KM. Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice. Circulation, 2004, 110(16): 2460-6.

    Figure 1Traditional risk factors include age, male sex, dyslipidemia, hypertension, smoking, and diabetes. More recently identified risk factors include obesity and a sedentary lifestyle.

    Figure 2In order to understand AS, one must understand the structure and function of the artery.The artery has three structural components: adventitia (which carries blood and nerve supply to the artery itself); media (comprised of smooth muscle, which controls vascular tone); intima (a basement membrane covered by endothelium which regulates hemostasis, thrombosis, vascular tone and permeability).The intima is the site of AS.

    Figure 3There are six stages of development of AS:Grades I IV: accumulation of lipids, first intracellularly, then extracellularly;Grade V: fibrosis around the lipid core forming an atherosclerotic plaque;Grade VI: complicated plaque (rupture, clot or bleed) leading to a clinical event.

    Figure 4:During AS, the integrity of the endothelium is compromised which results in: increased permeability, which facilitates the penetration of the intima by atherogenic lipoproteins;increased adhesion, which facilitates migration of monocytes into the subendothelium;diminished vasodilation, which compromises hemodynamic control.

    Figure 5Monocytes penetrate the intima and are transformed into macrophages and eventually cholesterol-rich foam cells. These activated macrophages scavenge and ingest oxidized low-density lipoprotein (LDL) in the subendothelial space. The progressive accumulation of lipids (intra- and extracellular) forms the fatty streak.

    Figure 6The growing fatty streak eventually forms the lipid core, which becomes isolated by the progressive formation of a fibrous cap. The fibrous cap contains collagen, proteoglycans and activated smooth muscle cells. The sturdier the cap, the less likelihood there is of plaque rupture.

    Figure 7Further lipid accumulation in the lipid core results in cell death (apoptosis).

    Figure 17Excessive atherogenic lipoproteins penetrate the intima from the bloodstream and are oxidized by free radicals in the subendothelium.oxidized LDL induces formation of adhesion molecules on the cell surface of the endothelium; monocytes are captured from the bloodstream by adhesion molecules and enter the subendothelial space; monocytes penetrate the intima and differentiate into macrophages which bind and absorb oxidized LDL via the non-regulated scavenger receptor.As macrophages accumulate cholesterol esters (CEs) they transform into foam cells.

    Figure 18Atherogenic lipoproteins (LDL or other apo B-containing lipoproteins) penetrate the intima. This renders them susceptible to oxidation the auto-oxidation lipid cycle. Oxidized LDL contains modified apo B which is not recognized by the normal receptors. Instead, it is recognized by the non-regulated scavenger receptor on the activated macrophage.

    Figure 19Oxidized LDL contains large amounts of cholesterol ester (CE). When macrophages are full of CE they secrete cytokines (IL-6, CRP, TNFa) which, in turn, induce vascular inflammation, cell recruitment, and weakening of the fibrous cap.

    Figure 8The key event in transformation of a stable plaque to an unstable plaque is rupture, which results in either partial or complete occlusive thrombosis.

    Figure 9Factors which play a key role in increasing plaque vulnerability. These include: lipid core formation; parietal vascular inflammation; thinning of the fibrous cap; thrombus formation.

    Figure 10Macrophages play a key role in the formation of a vulnerable plaque. This is achieved because they: liberate cytokines, which cause vascular wall inflammation; produce Tissue Factor (TF), which results in further cell recruitment; decrease fibrous cap resistance.

    Figure 11Activated macrophages release pro-inflammatory cytokines (IL-6, IL-1, TNFa). Cytokines increase hepatic fibrinogen expression and hence plasma concentration. The risk of cardiovascular disease increases with increasing fibrinogen concentrations.

    Figure 12Macrophages weaken the fibrous cap by releasing metalloproteases. This release results in: degradation of the fibrous cap around the lipid core; degradation of connective tissue within the lipid core.

    Figure 14Tissue Factor initiates the coagulation cascade, which culminates in thrombus formation. It is released from platelets and endothelium as well as activated macrophages.

    Figure 22Smoking increases the formation of oxidative free radicals, which raises the level of oxidized LDL. Nicotine has several direct effects, which include: increased cytokine production (which raises the level of vascular inflammation); direct cytotoxicity; vasospasm.

    Figure 23Atherogenic lipoproteins (e.g. LDL, apo B-rich particles like Lp-B:C-III) penetrate the arterial wall and induce: expression of adhesion molecules (which capture monocytes which then migrate into the intima); differentiation of macrophages (which release inflammatory cytokines); increased lipoprotein capture and penetration.