PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM DISORDERS

1. PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM DISORDERS Mehtap KACAR KOÇAK M.D. PhD Pathophysiologist

2. Learning Objectives • Describe to Cell adhesion molecules • Describe to injury of ischemia-reperfusion • Describe to atherosclerosis • Describe to hypertension • Ischemic heart diseases • Myocardial infarction • Heart failure • Cor pulmonale (right heart failure) • Rheumatic Heart Disease

3. INTEGRATING CELLS INTO TISSUES • Junctions: • Cell to cell • Gap junction • Tight junction • Anchoring junction • Cell to matrix • Focal adhesions • Hemidesmosomes

4. The appearance of multicellular organisms allows specialization of cells and formation of organs. • A special matrix, the extracellular matrix, ECM, fills out the space between cells • ECM also binds cells together, acts as reservoir for growth factors and hormones, and creates an environment in which molecules and cells can migrate. • By means of cell adhesion molecules, CAMs, cells are capable of recognizing each other • Plasma membrane receptors take care of cell-ECM interactions

5. Junctions Figure 3-14: Types of cell junctions

6. Key Junction Proteins: Connexin, cadherins, occludin & integrins

8. CELL-CELL ADHESION MOLECULES(NONJUNCTIONAL MECHANİSM) • Cadherins • Ig superfamily CAMs • Selectins • Integrins

9. CADHERINS • A family of Ca2+-dependent CAMs • Ca2+ causes dimerization of Cadherins • The binding is homophilic

10. IMMUNOGLOBULİN (Ig) FAMİLY MEMBERS: • Include: • * ICAM-1(Intracellular adhesion molecule 1), • * ICAM-2 (Intracellular adhesion molecule 2), • * VCAM-1 (Vascular cell adhesion molecule-1) • * PECAM-1(Platelet Endothelial Celladhesion molecule 1) • Structure:type 1 transmembrane glycoproteins • containing Ig homology domains

11. Expression patterns of Ig adhesion molecules: • IL-1 and TNF upregulate ICAM-1 and VCAM-1 expression on endothelium. • ICAM-2 is expressed constitutively on the endothelial surface. • PECAM-1 is expressed constitutively on endothelial cells at intercellular junctions and on leukocytes.

12. Ligands of Ig adhesion molecules: ICAM-1, ICAM-2 and VCAM-1 bind leukocyte integrins.

13. Selectins: • Three highly homologous members: • endothelial (E), platelet (P) and leukocyte (L) • Structure: type 1 transmembrane glycoproteins • E- and P-selectins are expressed by endothelial cells. • L-selectin is expressed by leukocytes. • P- and L-selectins are expressed constitutively. • Cytokines (IL-1 and TNF) upregulate the transcription of E- and P-selectins. • P-selectin is stored in cytoplasmic granules and a variety of stimuli can induce rapid translocation to the cell surface (within seconds).

14. Expression patterns of endothelial cell adhesion molecules: Inducible Stored in Constitutively expression cytoplasm expressed E-selectin P-selectin ICAM-2 VCAM-1 PECAM-1 ICAM-1

15. (Leukocyte) integrins: • Integrins are heterodimeric transmembrane proteins composed of alpha and beta chains. • Integrins provide a link between the cell cytoskeleton and the extracellular matrix. • Integrins are clustered in focal adhesion complexes.

16. Adhesion molecules relevant to inflammation: • Adhesion molecules are proteins with structural domains that mediate the adhesion of leukocytes to endothelial cells. • Adhesion molecules are proteins that contain structural domains. • Each adhesion molecule can bind one or several ligands or counter-receptors.

17. Leukocyte integrin ligands: • Leukocyte integrins bind members of the Ig gene superfamily as well as other proteins. • Integrin Counter-receptors • L2 ICAM-1, ICAM-2 • (LFA-1, CD11a/CD18) • M2 ICAM-1, fibrinogen, iC3b • (Mac-1, CD11b/CD18) • 41 VCAM-1, fibronectin CS-1 • (VLA-4, CD49d/CD29)

18. Endothelial Cell Activation Inflammatory cytokines (e.g., IL-1 or TNF) activate endothelial cells to express adhesion molecules. Activated Unactivated nonadhesive for leukocytes hyperadhesive for leukocytes

19. Integrin activation during inflammation NORMAL INFLAMMATION

20. Leukocyte adhesion cascade A sequence of activation and adhesion events leading to the extravasation of leukocytes at the site of inflammation. • Capture and Rolling (Fast-slow)-Selectins • Firm Adhesion-Integrins • Transmigration • Block in any one of them greatly reduces leukocyte accummulation in the damaged tissue.

23. Leukocyte Adhesion Cascade. Capture and Rolling • Cytokines released by injury activate venular endothelial cells and induce them to express P-selectin (stored in Weibel-Palade bodies) on their surface which interacts with a glycoprotein on leukocytes. • As a result the leukocytes roll along the endothelium forming bonds at the leading edge and breaking them at the trailing one. • L-selectin expressed by leukocytes also participates in the rolling process.It may be necessary for the initial attachment to the endothelium. In absence of P-selectin rolling is less efficiently mediated by L-selectin. • E-selectin expressed by activated endothelial cells is required to slow down rolling of leukocytes and initiates stronger adhesion.

24. General mechanism of cell injury • The three common forms of cell injury are; • 1- hypoxic injury (and following reperfusion injury) • 2- reactive oxygen species (ROS) and free radical-induced injury • 3- chemical injury (CCl4)

26. ISCHEMIA - REPERFUSION INJURY • Hypoxia, or lack of sufficient oxygen, is the single most common cause of cellular injury. • Hypoxia can result from: • a decreased amount of oxygen in the air , • loss of Hb or Hb function, • decreased production of red blood cells, • diseases of the respiratory and cardiovascular system, • poisoning of the oxidative enzymes (cytochromes) within the cells. • The most common cause of hypoxia is ischemia (reduced blood supply).

27. Ischemic injury is often caused by gradual narrowing of arteries (arteriosclerosis), and complete blockage by blood clots (thrombosis). • Cellular responses to hypoxic injury have been extensively studied in heart muscle. • Within 1 minute after blood supply to the myocardium is interrupted, the heart becomes pale. • Within 3 to 5 minutes, the ischemic portion of the myocardium ceases to contract.

28. The abrupt lack of contraction is caused by a rapid decrease in mitochondrial phosphorylation, which results in insufficient ATP production. • Lack of ATP leads to an increase in anaerobic metabolism, which generates ATP from glycogen when there is insufficient oxygen.

30. Irreversible damage characterized by two events: • 1- lack of ATP generation because of mitochondrial dysfunction, • 2- major disturbances and damage in membrane function. • Acid hydrolases from leaking lysosomes are activated in the reduced pH of the injured cell and they digest cytoplasmic and nuclear components. • Leakage of intracellular enzymes into the peripheral circulation provides a diagnostic tool for detecting tissue-specific cellular injury and death using blood samples (troponin-MI, liver transaminases-hepatic injury)

31. Reperfusion injury • Restoration of oxygen, however, can cause additional injury called reperfusion injury. • Xanthine dehydrogenase, an enzyme which normally utilizes oxidized nicotinamide adenine dinucleotid (NAD+) as an electron acceptor, is converted during reperfusion with oxygen to xanthine oxidase.

32. During ischemic period, excessive ATP consumption leads to the accumulation of the purine catabolites hypoxanthine and xanthine ; • Which upon subsequent reperfusion and influx of oxygen are metabolized by xanthine oxidase to make massive amounts of superoxide and hydrogen peroxide. • In addition the highly reactive free radical nitric oxide is generated.

33. These radicals can all cause membrane damage and mitochondrial calcium overload. • Neutrophils are especially affected with reperfusion injury, and neutrophil adhesion to the endothelium enhances the process.

35. Free radicals and reactive oxygen species-induced injury • An important mechanism of membrane damage is injury induced by free radicals, especially ROS called oxidative stress. • Oxidative stress occurs when excess ROS overwhelms endogenous antioxidant systems. • Free radicals may be initiated within cells by : • 1- the absorption of extreme enerjy sources (UV, x-ray) • 2- endogenous (during normal metabolic process) • 3- enzymatic metabolismof exogenous chemicals or drug.

37. Free radicals and ROS, three are particularly important in regard to cell injury: • 1- lipid peroxidation • 2- alterations of proteins causing fragmentation of polypeptide chains, • 3- alterations DNA, including breakage of single strands..

40. CARDIOVASCULAR DISORDERS: Vascular Disease • Outlines: • Pathophysiology of Atherosclerosis • Pathophysiology of Hypertension

41. Arteriosclerosis • Arteriosclerosis is a chronic disease of arterial system characterized by abnormal thickening and hardening of the vessel walls. • In arteriosclerosis the tunica intima undergoes a series of changes that decrease the artery’s ability to change lumen size. • Smooth muscle cells and collagen fibers migrate into the tunica intima, causing it to stiffen and thicken.

42. Arteriosclerosis: Pathophysiology • General term for all types of arterial changes • Best for degeneration in small arteries and arterioles • Loss of elasticity, walls thick and hard, lumen narrows

43. Atherosclerosis • Atherosclerosis is a form of arteriosclerosis in which the thickening and hardening of the vessel is caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called plaque. • It is leading contributor to coronary artery and cerebrovascular disease.

44. Presence of atheromas Plaques Consist of lipids, cells, fibrin, cell debris Lipids usually transported with lipoproteins Atherosclerosis: Pathophysiology

45. Consequences of Atherosclerosis

46. Lipoproteins and Transport

47. Atherosclerosis--Diagnosis • Analysis of serum lipids: • Total cholesterol, triglycerides, LDL, HDL • LDL • High cholesterol content • Transports cholesterol liver  cells • Dangerous component • HDL • “good” • Low cholesterol content • Transports cholesterol cells  liver

48. Atherosclerosis—Risk Factors • Age • Gender (Male) • Genetic factors • Obesity, diet high in cholesterol, animal fats • Cigarette smoking • Sedentary life style • Diabetes mellitus • Poorly controlled hypertension • Smoking • LDL↑ • HDL↓ • hyperhomocystinemia • CRP ↑ • Serum fibrinogen ↑ • Oxidative stress • Peridontal disease

49. Pathophysiology of atherosclerosis • Atherosclerosis is an inflammatory disease. • Atherosclerosis begins with injury to the endothelial cells that line artery walls. (Risk factors!!!) (remember leukocyte adhesion) • Pathologically the lesions progress from: endothelial injury and dysfunction to fatty streak to • fibrotic plaque to • complicated lesions.

50. Once injury has occured, endothelial dysfunction and inflammation lead to the following events: • 1. injured ECs become inflamed and cannot make normal amounts of antithrombotic and vasodilating cytokines. • 2. numerous inflammatory cytokines are released, including TNF-α, IF-γ, IL-1, toxic oxygen radicals, and heat shock proteins.