(653g) Feedback Effects of Extracellular Matrix Composition On AMPK Signaling Pathway: Pathway to Novel Drug Therapeutics Targeting Atherosclerosis | AIChE

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(653g) Feedback Effects of Extracellular Matrix Composition On AMPK Signaling Pathway: Pathway to Novel Drug Therapeutics Targeting Atherosclerosis

Authors 

Shyy, J. J. Y. - Presenter, University of California, Riverside


Table 1. The Table summarizes biomarkers that characterize atheroprotective, atherogenic, and atherosclerotic stages of blood vessels.

Atheroma is initiated and
progressed in the unhealthy and artheroprone region of the blood vessel. During the process, the collagenous
subendothelium (in the command of signaling pathways) is converted to a
fibrillar subendothelium. This process involves the deposition of fibronectin
and fibrinogen which alters the release of NO and the compliance of the vessel
wall.[2] Appropriate ECM composition establishes the functioning of
the endothelial signaling pathways in the vascular intima. In this work, we use
immunocytochemical methods that employ the distinct variations in extracellular
matrix to study the characteristic behavior of endothelial cells in
atheroprotective and atherogenic stages as shown in Table 1. We hypothesize that owing to different ECM
configuration, AMP modified protein kinase (AMPK) phosphorylation will vary
with flow.

            

Figure 1. The Figure shows the correlation of blood flow parameters at the endothelial cell monolayer to levels of integrin pair configurations, extracellular matrix, and AMPK signaling pathway in an endothelial cell.

For each experiment, the sterilized flow
circuit is maintained at 37°C, ventilated with 95% humidified air - 5% CO2,
and connected to the peristaltic pump. A parallel-plate flow channel is used to
impose laminar flow at 12 dyne/cm2 for time intervals on confluent
monolayer of endothelial cells (ECs). The contribution of extracellular matrix for atheroprone,
atherogenic, and atherosclerotic stages of the vasculature and their effects on
AMPK signaling pathway is explored through these in-vitro experiments (Figure 1).

Exploring the stress-related AMPK signaling pathway provides
striking insights into the onset and progression of atherosclerosis. A possible
feedback response between NO production and ECM is identified.

Keywords: Atherosclerosis, Extracellular matrix, Signaling
pathway

References:

[1] Shyy JYJ.
Extracellular Matrix Differentiating Good Flow versus Bad Flow. Circulation
Research 2009;104:931-932.

[2] Hahn C, Orr
AW, Sanders JM, Jhaveri KA, and Schwartz MA. The Subendothelial Extracellular
Matrix Modulates JNK Activation by Flow. Circulation Research
2009;104:995-U180.

[3] Stenman S, Vonsmitten K, and Vaheri
A. Fibronectin and Atherosclerosis. Acta Medica Scandinavica 1980:165-170.

[4] Levenson J, Giral P, Razavian M, Gariepy J, and Simon
A. Fibrinogen and Silent Atherosclerosis in Subjects with Cardiovascular
Risk-Factors. Arteriosclerosis Thrombosis and Vascular Biology
1995;15:1263-1268.

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