Understanding Age-Related Changes in Vascular Endothelium and Their Pathophysiological Implications

1. MCB 135K: Discussion

2. Significance of Age Changes in the Vascular Endothelium*Table 16-2, page 293* • Endothelial cells line the internal wall (intima) of the blood vessels. • While the muscle cells and the elastic fibers in the vascular wall regulate blood vessel motility (contraction and relaxation), the endothelial cells, serve as protective lining against trauma, infections, etc, • Endothelial cells undergo significant changes with aging indicative of abnormal function. • These alterations by themselves may induce pathology or may predispose with other factors to atherosclerosis

3. Significance of Age Changes in the Vascular Endothelium*Table 16-2, page 293* • Endothelial cells undergo significant changes indicative of abnormal function • The imbalance of vascular tone is manifested by increased vasoconstriction Endothelins EDRF, NO • Vascular integrity (cell proliferation and migration, wall remodeling) and injury repair through local growth factors are impaired VEGF Cytokines • Maintenance of blood fluidity is disrupted with increased cell adherence, blood coagulation, and thrombogenic properties Cytokines • These alterations by themselves may induce pathology or may predispose with other factors to atherosclerosis

4. Table 16-8: Theories of Atherosclerosis • Lipid accumulation • Myoclonal • Thrombogenic • Inflammation • Free Radicals **See page 299**

6. High homocysteinemia and Protein C

7. Lipids and Apolipoproteins • Major Categories • Risk Factors in Atherosclerosis • Lipoprotein Synthesis • Apolipoproteins • Lipolytic Enzymes • Receptors

8. Lipids and Apolipoproteins • Categories • Chylomicrons and VLDL • High triglycerides • IDL and LDL • High cholesterol • HDL • High proteins • High phospholipid

10. Lipids and Apolipoproteins • Risk Factors • Total cholesterol to HDL ratio above 4.0 • Family history • Elevated LDL; Low HDL • Diabetes Mellitus • Age • Hypertension • Obesity • Smoking

11. Lipoprotein Synthesis • Intestine • CM • Nascent HDL • Liver • VLDL • IDL • LDL • Nascent HDL

12. Apolipoproteins • Definition: • Markers on lipid cell surface that determines metabolic fate of lipids • Roles in Metabolism • apoA-I • HDL • Reverse Cholesterol Transport • apoB-100 • VLDL, IDL, LDL • Sole protein on LDL • Necessary for assembly and secretion in liver • Ligand for LDL receptorapoA-I is important in reverse cholesterol transport (review figure 17.3) • Process whereby lipid free apoA-I and subclasses of HDL mediate the removal of excess cholesterol

13. Apolipoproteins and RCT • apoA-I is important in reverse cholesterol transport (review figure 17.3) • Process whereby lipid free apoA-I and subclasses of HDL mediate the removal of excess cholesterol

14. Enzymes • Lipoprotein Lipase • Catabolizes CM and VLDL produces glycerol and fatty acids • Requires apoC-II for activation • Hepatic Triglyceride • LCAT • Essential for normal maturation of HDL • Associates with discoidal HDL and is activated by apoA-I • Forms hydrophobic cholesteryl ester that moves to core and gives spheroid shape (active)

15. Receptors • LDL • Responsible for internalization of LDL • Also known as apoB-E receptor • Regulates cholesterol synthesis • Macrophage Scavenger (SR-A1) • Recognizes oxidized LDL • Role in atherogenesis • SR-B1 • Docking protein for HDL • Role in selective uptake for steroid hormone production • Role in catabolism and excretion from liver

16. Exercise and Aging • Cardiovascular Fitness • Metabolic Fitness • Muscular Strength • Anti-oxidant defenses

17. Exercise and Aging • Cardiovascular Fitness • Maximal oxygen consumption • VO2 Max increased by regular exercise • Declines with aging • Decreases morbidity • Decreases mortality

18. Exercise and Aging • Metabolic Fitness • Control age related increases in body fat • Decrease risk of diabetes • Maintain Ideal BMI • Exercise at 45-50% of VO2 Max to facilitate fat loss (utilize fat as energy source)