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
2. Mxodifiable risk factors: Include Hypertension, Diabetes
mellitus, Cigarette smoking, some types of infections, CReactive Protein, Homocysteine, Lipoprotein(a), Elevated
Diabetes precursor
Oxidative stress
Endothelial cell
Erectile dysfunction
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
Endothelial denudation
Enhance End. Adhesiveness for
leukocyte + platelet+ alter local
vascular Anticoagulant
Lipoprotein Retention
Inflammation R
Lipoprotein lipase increase
adherence of LDL invitro
Macrophage engulf
deposited LDL
Micro aggregation
Scavenger R of macrophege
Modified LDL (ox LDL)
Lipid laden
(foam cell)
vasoctive agent,
Inflammation R
Migration of SMC
into intima
Proliferates to form
intermediate lesion
Cytokines ,
GF and proteolytic enz
Lead to
Biological Functions of nitric oxide in
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
Medications commonly prescribed in the treatment of
atherosclerosis include anti-hypertensives and cholesterol reducing
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
Statins inhibit hepatic synthesis of apolipoprotein B100 and
reduce the synthesis and secretion of triglyceride-rich
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
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)