Rapamycin attenuates atherosclerosis induced by dietary cholesterol in apolipoprotein-deficient mice through a p27 Kip1 -independent pathway.
Activation of immune cells and dysregulated growth and motility of vascular smooth muscle cells contribute to neointimal lesion development during the pathogenesis of vascular obstructive disease. Inhibition of these processes by the immunosuppressant rapamycin is associated with reduced neointimal thickening in the setting of balloon angioplasty and chronic graft vessel disease (CGVD). In this study, we show that rapamycin elicits a marked reduction of aortic atherosclerosis in apolipoprotein E (apoE)-null mice fed a high-fat diet despite sustained hypercholesterolemia. This inhibitory effect of rapamycin coincided with diminished aortic expression of the positive cell cycle regulatory proteins proliferating cell nuclear antigen and cyclin-dependent kinase 2. Moreover, rapamycin prevented the normal upregulation of the proatherogenic monocyte chemoattractant protein-1 (MCP-1, CCL2) seen in the aorta of fat-fed mice. Previous studies have implicated the growth suppressor p27(Kip1) in the antiproliferative and antimigratory activities of rapamycin in vitro. However, our studies with fat-fed mice doubly deficient for p27(Kip1) and apoE disclosed an antiatherogenic effect of rapamycin comparable with that found in apoE-null mice with an intact p27(Kip1) gene. Taken together, these findings extend the therapeutic application of rapamycin from the restenosis and CGVD models to the setting of diet-induced atherosclerosis. Our results suggest that rapamycin-dependent atheroprotection occurs through a p27(Kip1)-independent pathway that involves reduced expression of positive cell cycle regulators and MCP-1 within the arterial wall.
Castro
Claudia
C
Laboratorio de Biología Vascular, Departamento de Patología y Terapia Molecular y Celular, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, C/Jaime Roig 11, 46010, Valencia, Spain.
Campistol
Josep M
JM
Sancho
David
D
Sánchez-Madrid
Francisco
F
Casals
Elena
E
Andrés
Vicente
V
D000818:Animals; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology; D001053:Apolipoproteins / Q000172:deficiency*; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000032:analysis / Q000502:physiology*; D018932:Chemokine CCL2 / Q000032:analysis; D002791:Cholesterol, Dietary; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000032:analysis; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology; D015854:Up-Regulation
D001053:Apolipoproteins; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D007166:Immunosuppressive Agents; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus