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G(-670)-> A. polymophism in the promoter of the fas gene is a riskG(-670)-> A. polymophism in the promoter of the fas gene is a risk
factor for myocardial infarction --Miyuki Onishi et al.factor for myocardial infarction --Miyuki Onishi et al.
Fas is a receptor that mediates apoptosis which is a critical event for
eliminating activated macrophages.
154 subject with recent MI, 462 control.
Fas expression was detected on peripheral blood mononuclear cells.
A/G polymorphism of the fas gene significantly
different between MI and controls.
Leukemia inhibitory factor significantly suppressed the
levels of Fas expression in AA genotype subjects, no
effect in subjects with GG genotype.
Conclusion: The A allele of G/A polymorphysm in the promoter
region (-670-A) of the Fas gene is a new genetic risk factor of MI via
modulation of Fas expression
Immunoglobulin Treatment Suppresses AtherosclerosisImmunoglobulin Treatment Suppresses Atherosclerosis
in Apolipoprotein E Knockout Mice via the FC portionin Apolipoprotein E Knockout Mice via the FC portion
--Zhuyi Yuan et al--Zhuyi Yuan et al
IG is used for the treatment of immune-mediated disease.
ApoE mice fed with high fat diet.
IP injection of Human IG or F(ab’)2
fragments of IG at 8 weeks and 16 weeks
IG markedly suppressed Fatty streak formation
and fibofatty plaque and macrophage accumulation
F(ab’)2 has no effect.
IG therapy markedly suppressed atherosclerosis via the Fc
portion of IG.
The suppression is associated with marked reduction
of macrophage density in the region.
NF-kB Inhibition Reduces Pro-Inflammatory Molecule ExpressionNF-kB Inhibition Reduces Pro-Inflammatory Molecule Expression
and Attenuates Atherosclerosis in ApoE-/- miceand Attenuates Atherosclerosis in ApoE-/- mice
Yutaka Furukawa et al.Yutaka Furukawa et al.
Activation of NF-kB induces pro-inflammatory molecule mRNA
including MCP-1 and VCAM-1.
NF-KP inhibitor(NF-kB1) was used.
Male C57BL/6 apoE-/- mice were fed a western type diet.
Administ. Of NF-kB1 or vehicle for 10 weeks.
Immunohistochemistry: macrophage accumulation and VCAM-1
Real-time PCR showed that VCAM-1 and MCP-1 mRNA
expression in the aorta decreased
NF-kB may be a therapeutic target in the prevention of
Cholesterol Regulated Genome wide approchCholesterol Regulated Genome wide approch
Using microarray to identify genes regulated by dietary cholesterol in the
Method: C57BL/6J mice
W/o cholestrol With 0.5% cholesterol.
Pooled or individual hybridize with array.
Retain genes with signal > 250, Fold>1.6.
Unigen cluster tools, got 88 probe set
* There are 15 starts in Human Genome. He
introduced Star D4,5,6 from the probe set.
MMP-8: Evidence of a New Collagenolytic Pathway in AcuteMMP-8: Evidence of a New Collagenolytic Pathway in Acute
Plaque DisruptionPlaque Disruption
Lan Loftus et al.Lan Loftus et al.
MMP-8 is the enzyme that preferentially degrades type I collagen.
Aim: quantify the level of MMP-8 in carotid plaques.
Plaque from 75 patients undergoing carotid endarterectomy.
MMP-8 level were quantified using ELISA.Immunostaining.
All patient undergo Td monitoring to detect spontaneous
Results: MMP-8 level in plaque higher in patients with recent symptoms and
There is significant relation between level of MMP-8 and MMP-9.
Elevate of MMP-8 and together with MMP-9 have the potential to
degrade all components of extracellular matrix and represent a target
for pharmacotherapy to prevent acute plaque disruption.
Enhanced Migration and Matrix Degradation by ChlamydiaEnhanced Migration and Matrix Degradation by Chlamydia
pneumoniae-Infected Monocytes via the plasminogen andpneumoniae-Infected Monocytes via the plasminogen and
EMMPRIN/MMP Activation system. Implications for PlaqueEMMPRIN/MMP Activation system. Implications for Plaque
Rupture. -- Roland Schmidt et al.Rupture. -- Roland Schmidt et al.
The effects of C.pn initiation of matrix degrading activity in
monocytes with regard to the role of EMMPRIN, Extracellular MMP-
Method and results:
MonoMac6 cells or isolated monocytes
with C pn for 48 hrs.
C.pn. Induces monocytic matrix degradation and matrix invasion via
activation of the plasminogen and the EMMPRIN/MMP activative
system. Which may contribute to the development of cardiovascular
complications such as plaque rupture.
Angiotensin II mediates production of Matrix Metalloproteinases-1Angiotensin II mediates production of Matrix Metalloproteinases-1
and –9 by Monocytes: Implication for Atherosclerotic Plaqueand –9 by Monocytes: Implication for Atherosclerotic Plaque
Rupture – Min P Kim et al.Rupture – Min P Kim et al.
Hypothesis: AngII enhances the production of monocyte MMP-1 and
MMP-9, two major MMPs associated with plaque rupture.
Method: Elutration of human primary blood monocytes cultured with
Levels of MMP-2,MMP-9 in supernatant were determined by
ELISA or western analysis.
Conclusion: AngII has a central role in the production of MMP-1 and
MMP-9 by monocytes. It provide insight into the association between
hypertension and acut coronary sydrome and a possible mechanism by
which angiotensin converting enzyme inhibitor and aspirin may reduce
the risk for heart attacks.
Organization of HUPO and opportunity for proteomic research on aOrganization of HUPO and opportunity for proteomic research on a
globe wide level as well as in the USAglobe wide level as well as in the USA
–Sam Hanash–Sam Hanash
High dynamic compartment
Most direct relevant to function
High relevant to biological fluid
Regulated at transcriptional level
and post-transcription level.
Field of Proteomics
Goal: Comprehensive analyze of all of
protein constituents of a cell or tissue.
Tracking of protein traffic.
Tracking of post-translational modifiers
Types of Technology:
*present focus on subcellular
Exp: Cell surface protein which is
important for diagnostics and
Tag cell surface protein with Biotin.
Then solubolize cell membrane.
Run this cell lysate through Avidin
column to capture Biotin related
cell surface protein. Load onto 2D
gel for protein separation. Digest
all interest band and identify them
Combination of electrophoresis
and chromatography to fractionate
one lysate into a lot of protein.
Identify antigen in
Identify drug binging protein.
Studies of protein interaction
1. Reesources and tech.
2. Model cells.
3. Plasma proteomic
Model cells and tissure:
Gene Expression Profiles during Human Atherogeeneesis; A RoleGene Expression Profiles during Human Atherogeeneesis; A Role
for the LIF-Receptor in Lesion Progression --Birgit Faber et alfor the LIF-Receptor in Lesion Progression --Birgit Faber et al
Study: profle large-scale expression on early, advanced but stable
and ruptured atherosclerotic plaques.
Method and results:
1. 3 early stage plaque and 3 ruptured plaque mRNA -> run on
microarray ( Incyte Genomics Inc) -> 105 gene upregulated and 88
genes down regulated, phase of atherogenesis vs. stable plaques. 79
gene up and 65 gene down after plaque rupture.
2. Hybridize CDNA of (Pooled n=3 for each) normal artery, early
lesions, stable lesions and rupture lesion with custome made cDNA
expression array. LIF receptor enhanced in plaque rupture. RT-PCR
revealed LIF receptor MRNA expression in 1/3 normal arteries, ¼
early leesions,8/10ruptured plaque specimens. LIP receptor protein
expression located in smooth muscle cells and macrophages of
This expression profile suggests a role for the LIF-receptor in the
progression of human atherosclerosis.
Cyr61(CNN1) and Connective Tissue Growth Factor(CNN2) areCyr61(CNN1) and Connective Tissue Growth Factor(CNN2) are
Novel Ligands of Inteegrin aMB2 on Peeripheral Blood MonocytesNovel Ligands of Inteegrin aMB2 on Peeripheral Blood Monocytes
-- Joseph M Schober et al.-- Joseph M Schober et al.
Cysteine-rich 61(Cry61,CCN1) and connective tissuee growth
factor(CTGF, CVN2) are growth factor-incucible immediate-
early gene products found in atherosclerotic lesions,
restenosed blood vellel walls and healing cutaneous wounds.
Study: Examinee monocyte interaction with Cyr61 and
CTGF. Because monocyte adhesion and transmigration are
important for athereosclerosis, inflammation and wound
Results: monocyte adhesion to Cyr61 is specificaly blocked
by antibodies directed against the integrin aM and B2 subunit
indicating that integrin serves as an adhesion recptor on
monocyte for thesee CCN protein. Monocyte adhesion to
Cyr61 induces the expression of inflammatory mediators
including IL-1, IL-8 MCP-1,MRP8 and MRP14.
Suggestion: these finding indicated that Cyr61 and CTGF aree
novel ligands of integrin aMB2 on monocytes and suggestion
an important pathophysiologic role of monocyte adhesion to