ATHEROSCLEROSIS

Atherosclerosis Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. Risk factors are 1. Non modifiable risk factors: Include age, sex, and genetic factors 2. Mxodifiable risk factors: Include Hypertension, Diabetes mellitus, Cigarette smoking, some types of infections, C- Reactive Protein, Homocysteine, Lipoprotein(a), Elevated fibrinogen

DiabetesDiabetes HypertensionHypertension Oxidative stress Endothelial cell injury VasoconstrictionVasoconstriction Erectile dysfunction outcomeoutcome DyslipidemiaDyslipidemia TobaccoTobacco ThrombosisThrombosis AtherosclerosisAtherosclerosis precursorprecursor

Pathogenesis of atherosclerosis Hypotheses of atherogenesis Three distinct hypotheses have emerged that are currently under active investigation. : 1) the response-to-injury, 2) the response-to-retention, and 3) oxidative modification

Modified LDL (ox LDL ) Scavenger R of macrophege Enhance End. Adhesiveness for leukocyte + platelet+ alter local vascular Anticoagulant Endothelial denudation Cytokines, vasoctive agent, G F Inflammation R Migration of SMC into intima Proliferates to form intermediate lesion Macrophage engulf deposited LDL Lipid laden (foam cell ) Necrosis Cytokines, GF and proteolytic enz Lead to Lipoprotein Retention Lipoprotein lipase increase adherence of LDL invitro Micro aggregation Inflammation R Atherosclerosis

Biological Functions of nitric oxide in atherosclerosis Nitric oxide has many physiological actions that can be interpreted to be potentially antiatherosclerotic. It inhibits 1) platelet aggregation and adherence to endothelial cells, 2) monocyte adherence to endothelial cells, 3) the expression of the monocyte chemoattractant protein, 4) vascular smooth muscle cell migration and proliferation and 5) the in vivo intimal proliferative response to ballon injury.

Biological Functions of Nitric Oxide eNOS (Endothelial Nitric Oxide Synthase) is the protein that helps produce NO and is a marker of endothelial cell function

Treatment of atherosclerosis Treatment of atherosclerosis relies heavily on the reduction of risk factors. Lifestyle factors are also of greatest importance in the treatment of atherosclerosis 1-Lifestyle change: Lifestyle changes such as smoking cessation, Regular exercise, Maintenance of appropriate body weight contribute significantly to the treatment of most forms of cardiovascular diseases 2-Medications Medications commonly prescribed in the treatment of atherosclerosis include anti-hypertensives and cholesterol reducing drugs

A.Anti-hypertensives: While anti-hypertensives do not control the process of atherosclerosis, they are successful in controlling one of the primary side effects. These drugs include calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers B. Cholesterol reducing drugs: Keeping serum cholesterol level in the normal range not only helps prevent heart attacks and strokes but may also prevent the progression of atherosclerosis. These drugs include: Statins, Bile-Acid–Binding Resins, Nicotinic Acid, Fibrates, Cholesterol absorption inhibitors (ezetimibe)

Mechanism of action of statins :  nhibition of HMG CoA : Statins inhibit HMG-CoA reductase, the enzyme that converts HMG-CoA into mevalonic acid, a cholesterol precursor (the rate limiting step in cholesterol synthesis)  Statins inhibit hepatic synthesis of apolipoprotein B100 and reduce the synthesis and secretion of triglyceride-rich lipoproteins  Reduction of LDL susceptibility towards oxidation

Pleiotropic effects of statins :  statins plieotropic effects are dissociated from their hypolipidemic effects and these effects include  1- anti inflammatory effects : statins decrease serum level of C-Reactive protien and decrease adhesion and chomotactic molecules  2- immunomodulatory role : statins can decrease T-cell proliferation and reduce inflammatory cytokine production like tumor necrosis factor-α  3- statind improve endothelial dysfunction : by increasin increasing the bioavialability of nitric oxide which has vasodilator, antithrombotic and anti-proliferative properties

 4-statins have antioxidant properties  5- statins stabilizes pleaques and prevent their rupture  6- Statins may impede thrombogenesis by inhibiting the activation of the extrinsic coagulation pathway, by inhibiting platelet adhesion and aggregation  7-Statins have a potential role in regulating the sympathetic and vagal outflow in the central nervous system by enhancing NO synthesis in the endothelium and thus increase the vasodilatory response to acetylcholine and modulate the release and action of vasoconstrictors (e.g.endothelin and angiotensin II)