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Gene Array Study of Vulnerable
Atherosclerotic Plaque
In Apo E K/O Mice Plaques Prompted to
Rupture by Modified Falk Proc...
Morteza Naghavi, MD
Sadaf Anwar, MD
Mohammad Madjid, MD
Silvio Litovsky, MD
Rahul Mitra, MD
Hugh A. McAllister,MD
Frank D....
Rationales of the Study
• The basic mechanisms leading to plaque rupture in
terms of genomic changes are still in shadow
•...
Why Going to Gene Level?
Gene
Protein
Function
Sensitivity
Why is novel about this study?
•We are going to gene level, hence
having a higher probability of
detecting changes of inte...
Of Mice and Human
• We are looking into three models of:
Apo E K/O Mice
Human carotid plaques
Human coronary plaques
Examples of Genes of Interest:
Apoptosis Lipid
Metabolism
Interleukins MMPs
Thrombosis Aspartate
Endopeptidases
NO system ...
50 Apo E K/O mice age > 2 y
• Group A
45 mice for prompting to plaque rupture
• Group B
5 mice for control
Each Five Mice:
• L-NAME (N-nitro-L-arginine methyl ester)
(vasoconstriction)
• Cocaine (Hypertension, tachycardia)
• Xant...
Multi-Factor Approach
Cocaine
+ xanthine
+ xanthine oxidase
+ adrenaline
5 Mice are kept as controls
with no injection
At Day Seven:
• Mice are euthenized (Co2) and then
dissected
• Before day 7 Animals will be
monitored every 6 hours. If an...
• Choice: specialized device for cross-
sectional cutting of total mouse body
• If not available: mice are dissected and
a...
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
Gene array study of vp
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Gene array study of vp

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Gene array study of vp

  1. 1. Gene Array Study of Vulnerable Atherosclerotic Plaque In Apo E K/O Mice Plaques Prompted to Rupture by Modified Falk Procedure In Human Carotid Endarterectomized Plaques In Human Ruptured Coronary Arteries
  2. 2. Morteza Naghavi, MD Sadaf Anwar, MD Mohammad Madjid, MD Silvio Litovsky, MD Rahul Mitra, MD Hugh A. McAllister,MD Frank D. Kolodgie, MD Ward Casscells, MD James T Willerson, MD University of Texas-Houston Texas Heart Institute
  3. 3. Rationales of the Study • The basic mechanisms leading to plaque rupture in terms of genomic changes are still in shadow • There has been no animal of plaque rupture to date • An animal model offers a great opportunity to test new diagnostic and therapeutic approaches • Plaque vulnerability definition is at the center of doubt and argument. Gene studies may help in clearing this issue too.
  4. 4. Why Going to Gene Level? Gene Protein Function Sensitivity
  5. 5. Why is novel about this study? •We are going to gene level, hence having a higher probability of detecting changes of interest •We are using our rare clone of old (>2yr) Apo E K/O mice
  6. 6. Of Mice and Human • We are looking into three models of: Apo E K/O Mice Human carotid plaques Human coronary plaques
  7. 7. Examples of Genes of Interest: Apoptosis Lipid Metabolism Interleukins MMPs Thrombosis Aspartate Endopeptidases NO system MMPIs Cell Adhesion Molecules Cysteine Endopeptidases Nuclear factors and receptors Cathepsins … Serine Endopeptidases … ….
  8. 8. 50 Apo E K/O mice age > 2 y • Group A 45 mice for prompting to plaque rupture • Group B 5 mice for control
  9. 9. Each Five Mice: • L-NAME (N-nitro-L-arginine methyl ester) (vasoconstriction) • Cocaine (Hypertension, tachycardia) • Xanthine + xanthine oxidase (inflammatory response) • IL-1 beta (inflammatory response /septic shock) • Adrenaline (hypertension, tachycardia) • Methionine (direct cytotoxic effects destabilizing the plaque) • Buthionine sulfoximine (GSH inhibition, hypertension)
  10. 10. Multi-Factor Approach Cocaine + xanthine + xanthine oxidase + adrenaline
  11. 11. 5 Mice are kept as controls with no injection
  12. 12. At Day Seven: • Mice are euthenized (Co2) and then dissected • Before day 7 Animals will be monitored every 6 hours. If any of them is found dead in the middle of the experiment it will be assessed for evidence of plaque rupture
  13. 13. • Choice: specialized device for cross- sectional cutting of total mouse body • If not available: mice are dissected and atherosclerotic plaque from aortic root and arch from all mice are taken for histopathological assessment as well as mRNA study.

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