Site-specific atherogenic gene expression correlates with subsequent variable lesion development in coronary and peripheral vasculature.
OBJECTIVE
The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner.


RESULTS
Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (n=52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronary>thoracic aorta>>carotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronaries>thoracic aortae>carotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA(2) mRNAs) were only upregulated at 6 months in coronary arteries.


CONCLUSIONS
Variable gene expression, both in regard to the arterial bed and duration of disease, was associated with variable plaque development and progression. These findings may provide further insight into the atherosclerotic process and development of potential therapeutic targets.
Mohler
Emile R
ER
University of Pennsylvania, Philadelphia, PA 19104, USA.
Sarov-Blat
Lea
L
Shi
Yi
Y
Hamamdzic
Damir
D
Zalewski
Andrew
A
Macphee
Colin
C
Llano
Raul
R
Pelchovitz
Dan
D
Mainigi
Sumeet K
SK
Osman
Hashim
H
Hallman
Troy
T
Steplewski
Klaudia
K
Gertz
Zachary
Z
Lu
Min Min
MM
Wilensky
Robert L
RL
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006937:Hypercholesterolemia / Q000150:complications; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013311:Streptozocin; D013552:Swine
D018932:Chemokine CCL2; D007328:Insulin; D013311:Streptozocin; D002784:Cholesterol; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D020780:Matrix Metalloproteinase 9