2. Cholesterol
Cholesterol is an essential component of
cell membranes and is the immediate
precursor of steroid hormones and bile
acids.
The rate-limiting enzyme in cholesterol
biosynthesis in the liver is HMG-CoA
reductase.
4. Statins
Reversibly inhibit HMG-CoA reductase.
Binds to enzyme's active site and block
the substrate-product transition state of
the enzyme.
All statins competitively inhibit the
reductase.
5.
6. “Pleiotropic" effects of statins
cholesterol-independent effects
Inhibit l-mevalonic acid synthesis
Decrease in isoprenylation of signaling
molecules, such as Ras, Rho, and Rac
Leads to the accumulation of inactive
Ras and Rho in the cytoplasm.
7. Statin pleiotropy
Improvement of endothelial dysfunction
Reduced inflammatory response
Stabilization of atherosclerotic plaques
Reduced thrombogenic response
Inhibit vascular SMC proliferation.
Inhibit cardiac hypertrophy
Decrease in the incidence of ischemic
strokes
8. STATINS AND
ENDOTHELIAL FUNCTION
Important characteristic of endothelial
dysfunction is the impaired synthesis,
release, and activity of endothelial-
derived nitric oxide (NO)
10. Contd……………
Statins increase endothelial NO
production by stimulating and
upregulating endothelial NO
synthase (eNOS).
Inhibition of RhoA by statins
mediates the increase in eNOS
expression.
Prolong eNOS mRNA half-life
11. Antioxidant effects
; Inhibit the production of reactive oxygen
species (ROS), such as superoxide and
hydroxy radicals.
Statins attenuate angiotensin II–induced
free radical production in vascular
smooth muscle cells.
Inhibits Rac1-mediated NADH oxidaseInhibits Rac1-mediated NADH oxidase
activity.activity.
Downregulates angiotensin AT1 receptorDownregulates angiotensin AT1 receptor
expression.expression.
12. STATINS AND
ENDOTHELIAL PROGENITOR
CELLS
Increase the number of circulating endothelial
progenitor cells
Statins induce angiogenesis
Promotes the proliferation, migration, and
survival of circulating EPCs
Rapidly mobilize EPCs from the bone marrow
Accelerate vascular structure formation
Effects via Activation of phosphatidylinositol
3-kinase (PI3K)/protein kinase Akt and eNOS
13. STATINS AND SMOOTH
MUSCLE PROLIFERATION
Statins attenuate vascular
proliferative disease
Arresting cell cycle between the G1/S
phase transition
Inhibition of isoprenoid synthesis by
statins decreased PDGF-induced DNA
synthesis in vascular SMCs
14. STATINS AND PLATELET
FUNCTION
Inhibition of platelet aggregation
Statin-mediated upregulation of eNOS
Reduction in the production of TXA2
Statins inhibit tissue factor expression
by macrophages
Decrease cholesterol content of platelet
and erythrocyte membranes
15. STATINS AND PLAQUE
STABILITY
Contains thrombogenic materials in the lipid
core separated from the bloodstream by a
fibrous cap.
Secretion of proteolytic enzymes, such as
metalloproteinases by activated macrophages
may weaken the fibrous cap.
Plaque stabilizing properties of statins, are
mediated through a combined reduction in
lipids, macrophages, and MMPs
17. STATINS AND VASCULAR
INFLAMMATION
Atherosclerosis is a complex
inflammatory process.
Statins reduce the number of
inflammatory cells in
atherosclerotic plaques.
Inhibition of adhesion molecules.
Reduced levels of C-reactive protein.
18. EFFECTS OF STATINS ON
THE MYOCARDIUM
Inhibit cardiac hypertrophy
MECHANISM
Antioxidant mechanism involving
inhibition of Rac1 geranylgeranylation.
Statins inhibit angiotensin II–induced
oxidative stress
19. STATINS AND ISCHEMIC
STROKE
28% reduction in the incidence of ischemic
stroke ischemic stroke over 20,000 people
with cerebrovascular disease or other high-risk
conditions.
Attribute to effects of statins on endothelial
and platelet function.
Cerebrovascular tone and blood flow are
regulated by endothelium-derived NO.
Statins upregulate eNOS expression and
activity.
20. Contd…………
statins upregulate tissue-type plasminogen
activator
downregulate plasminogen activator inhibitor
( inhibition of Rho geranylgeranylation )
Anti-atherosclerotic and plaque-stabilizing
effects
anti-inflammatory actions and mobilization of
endothelial progenitor cells -Neuroprotection.
The growing fatty streak eventually forms the lipid core, which becomes isolated by the progressive formation of a fibrous cap. The fibrous cap contains collagen, proteoglycans and activated smooth muscle cells. The sturdier the cap, the less likelihood there is of plaque rupture.
