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Note Midterm - 4 March in class Note Signal peptide-A sequence of amino acids that determine whether a protein will be formed on the rough endoplasmic reticulum or on free ribosomes. Note: all protein synthesis begins on free ribosomes. Conversion of 70 mg/dl glucose to 3.9 mmol/L Lecture 5a 3 Feb. 2014 Atherosclerosis Pathology-5a Nutritional Intervention-5b Functional Food/Nutraceutical Approaches-5c Atherosclerosis-Pathology LDL and Lp(a) deposits lipid in artery wall HDL removes lipid from artery wall Roles of LCAT, LPL, CETP in these processes Aggregated platelets also clog up arteries Factors affecting atherosclerosis Blood Levels of concern-the more risk factors (eg obesity and in particular abdominal obesity) the lower the cut off points for LDL-c HDL-c < 0.90 mmol/L plasma LDL-c > 3.40 mmol/L plasma including oxidized LDL Lp(a) - > 20-30 mg/dl plasma Cholesterol > 5.20 mmol/L Triglycerides-fasting > 1.70 mmol/L plasma -post-prandial Factors affecting atherosclerosis Blood Levels of concern-the more risk factors (eg obesity and in particular abdominal obesity) the lower the cut off points for LDL-c Risk Category LDL-c level Cholesterol:HDL-c ratio > 20 %** < 2.0 mmol/L < 4.0 Moderate 11-19 % < 3.5 mmol/L < 5.0 Low < 10 % < 5.0 mmol/L < 6.0 High Risk ** or history of diabetes or any atherosclerotic disease - Can. J. Cardiol 22: 913-end September 2006 Factors affecting atherosclerosis Triglycerides and small dense LDL As plasma triglyceride levels rise there is a greater percentage of small dense LDL -small dense LDL is taken up very aggressively into artery wall Triglycerides and low HDL -this is due to low LPL activity Factors affecting atherosclerosis Macrophages Oxidation of LDL results in the binding of monocytes to the endothelial cells lining the vessel wall. These monocytes are activated and migrate into the endothelial space where they are transformed into macrophages, leading to further oxidation of the LDL. The oxidized LDL is taken up through the scavenger receptor on the macrophage, leading to the formation of foam cells. Factors affecting atherosclerosis -aggregated platelets also clog up the arteries Factors affecting atherosclerosis Platelets Collagen is the aggregation kick off followed by the proaggregatory ADP and TxA2 Aggregation affected by: Platelet membrane phospholipid fatty acid composition -cyclooxygenase produces prostaglandins -lipoxygenase produces leukotrienes -review arachidonic acid displacement Decreased platelet membrane fluidity -if cholesterol:phospholipid ratio increased -if degree of membrane fatty acid saturation increased -results in increased platelet aggregation Factors affecting atherosclerosis Platelets interactions with lipoproteins Interaction with lipoproteins HDL-lowers aggregation LDL-elevates aggregation Lp (a)-depresses platelet aggregation though also thought to inhibit plasminogen activation Factors affecting atherosclerosis Blood pressure damage vascular wall causing increased LDL influx Factors affecting blood pressure: -Water content of blood-renal function -Vasodilation -Vasoconstriction Values of concern - > 140 (systolic) or > 90 (diastolic) or > 140/90 Factors affecting atherosclerosis Obesity -measures waist circumference waist to hip and waist to height BMI skin folds underwater weighing apple/pear shape -obesity causes the following: -elevated blood pressure and renal disease -elevated plasma triglycerides -elevated plasma LDLc and sd LDLc -decreased plasma HDLc Factors affecting atherosclerosis Renal Disease -urea builds up in blood and is toxic to endothelium (results in reduced vasodilation) -renal disease causes further elevated blood pressure due to reduced water clearance from the blood and reduced vasodilation Factors affecting atherosclerosis Various Pathogens -chlamydia pneumoniae -cytomegalovirus -heliobacter pylori -these agents are hypothesised to inflame the endothelium thus permitting influx of LDL -the exact role if any of pathogens in atherosclerosis is yet to be worked on Factors affecting atherosclerosis -Nitric oxide-increased levels give vasodilation, antiplatelet effects Factors affecting atherosclerosis Genetics -HDL- LCAT, CETP -LDL- LDL receptor -VLDL- LPL (apo C-II-activation, C-III) inhibition) - -chylomicrons-LPL Genetics -Lp (a) – apo (a) -cholesterol- HMG-CoA reductase -platelets-cyclooxygenase and lipoxygenase Genetics -leptin (obesity) Genetics -immune response adequacy of response in part governed genetically-possible implications include the infection/inflammatory issues mentioned above Genetics -nitric oxide synthase -nitric oxide synthase gene polymorphisms affect level of this enzyme and hence nitric oxide levels
