Abstract
The objective of the present study was to assess the effects of the immunosuppressant rapamycin (Rapamune, Sirolimus) on both resistance vessel responsiveness and atherosclerosis in apolipoprotein E-deficient 8-week-old male mice fed a normal rodent diet. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation of isolated mesenteric bed, and atherosclerotic lesions were evaluated. After 12 weeks of orally administered rapamycin (5 mg.kg-1.day-1, N = 9) and compared with untreated (control, N = 9) animals, rapamycin treatment did not modify either NE-induced vasoconstriction (maximal response: 114 +/- 4 vs 124 +/- 10 mmHg, respectively) or ACh- (maximal response: 51 +/- 8 vs 53 +/- 5%, respectively) and SNP-induced vasorelaxation (maximal response: 73 +/- 6 vs 74 +/- 6%, respectively) of the isolated vascular mesenteric bed. Despite increased total cholesterol in treated mice (982 +/- 59 vs 722 +/- 49 mg/dL, P < 0.01), lipid deposition on the aorta wall vessel was significantly less in rapamycin-treated animals (37 +/- 12 vs 68 +/- 8 microm(2) x 10(3)). These results indicate that orally administered rapamycin is effective in attenuating the progression of atherosclerotic plaque without affecting the responsiveness of resistance vessels, supporting the idea that this immunosuppressant agent might be of potential benefit against atherosclerosis in patients undergoing therapy.
Highlights
Rapamycin (Rapamune®, Sirolimus) is an antifungal agent with antiproliferative and immunosuppressant properties used to prevent rejection of transplanted organs [1]
ApoE-deficient mice treated with orally administered rapamycin gained similar amounts of body weight and were as active as control mice
The endothelium-independent vascular smooth muscle relaxation to sodium nitroprusside (SNP) was unchanged by rapamycin treatment compared to control mice: maximal response (73 ± 6 vs 74 ± 6%, respectively) and logED50 (-5.78 ± 0.51 vs -5.31 ± 0.31 M, respectively)
Summary
Rapamycin (Rapamune®, Sirolimus) is an antifungal agent with antiproliferative and immunosuppressant properties used to prevent rejection of transplanted organs [1]. The primary vascular effects of this drug include the inhibition of smooth muscle and endothelial cell proliferation [3]. Abnormal vascular smooth muscle cell proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty [4]. Rapamycin has been shown to be effective in decreasing coronary artery restenosis in humans when eluted from implanted stents and, this treatment is commonly used in percutaneous coronary interventions [5,6]. Some studies, which focused on the understanding of the effects of this drug on vascular function, have shown that, in contrast to bare metal stents, rapamycin-eluting stents impair endothelial function, as indicated by an acetylcholine-induced coronary vasoconstrictive response in the proximal and distal stent segments [7,8]
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