Activation of the ROCK1 branch of the transforming growth factor-beta pathway contributes to RAGE-dependent acceleration of atherosclerosis in diabetic ApoE-null mice.
BACKGROUND
The multiligand RAGE (receptor for advanced glycation end products) contributes to atherosclerosis in apolipoprotein (Apo)E-null mice.


OBJECTIVE
To delineate the specific mechanisms by which RAGE accelerated atherosclerosis, we performed Affymetrix gene expression arrays on aortas of nondiabetic and diabetic ApoE-null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis.


RESULTS
We report that there is very little overlap of the genes that are differentially expressed both in the onset of diabetes in ApoE-null mice, and in the effect of RAGE deletion in diabetic ApoE-null mice. Pathway-Express analysis revealed that the transforming growth factor-beta pathway and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilitates the formation of atherosclerotic plaques in ApoE-null mice, and the mechanism by which deletion of RAGE ameliorates this effect. Quantitative polymerase chain reaction studies, Western blotting, and confocal microscopy in aortic tissue and in primary cultures of murine aortic smooth muscle cells supported these findings.


CONCLUSIONS
Taken together, our work suggests that RAGE-dependent acceleration of atherosclerosis in ApoE-null mice is dependent, at least in part, on the action of the ROCK1 (rho-associated protein kinase 1) branch of the transforming growth factor-beta pathway.
Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
De-xiu
DX
Bu
Vivek
V
Rai
Xiaoping
X
Shen
Rosa
R
Rosario
Yan
Y
Lu
Vivette
V
D'Agati
Shi Fang
SF
Yan
Richard A
RA
Friedman
Edem
E
Nuglozeh
Ann Marie
AM
Schmidt
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D004789:Enzyme Activation; D022001:Focal Adhesions / Q000201:enzymology; D020869:Gene Expression Profiling / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D019700:Thrombospondin 1 / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases