흰쥐의 경동맥 풍선 손상 모델에서 경구 Everolimus 투여에 의한 외막세포 활성화와 신내막 형성 감소 = Oral Everolimus Reduces Adventitial Cell Activation and Neointima Formation in Balloon-Injured Rat Carotid Artery

다국어 초록 (Multilingual Abstract)

Background and Objectives：Previous studies suggest that phenotypic conversion, proliferation and migration of adventitial fibroblasts after balloon injury have an important role in neointimal formation and vascular remodeling. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) reduces adventitial cell activation and neointimal formation in balloon-injured rat carotid arteries. Materials and Methods：Oral everolimus (1.25 mg/kg/day), or a matching placebo, was administered daily to 30 rats by gavage, starting 3 days before balloon injury. The treatment effects were assessed 3, 7 and 14 days after injury. Results：The oral everolimus group showed a significant reduction in adventitial cell proliferation at 3 days after injury and significant neointimal formation reduction compared to the control group at 7 and 14 days after injury (control group 0.06±0.01 mm2, everolimus group 0.01±0.01 mm2, p<0.01 and control group 0.28±0.06 mm2, everolimus group 0.08±0.03 mm2, p<0.01). Conclusion：Oral everolimus reduces adventitial cell activation and neointima formation in balloon injured rat carotid arteries.

국문 초록 (Abstract)

배경 및 목적：혈관 외막의 섬유모세포는 혈관 손상 후 근섬유모세포로 형질전환을 일으키고 증식하여 혈관 재형성 및 신내막형성에 중요한 역할을 하는 것으로 알려져 있다. 흰 쥐의 경동맥 풍선 손상 모델에서 rapamycin의 유도체인 everolimus를 경구로 투여하였을 경우 외막세포의 활성화와 신내막 형성의 억제 효과가 있는지 알아보고자 하였다.방 법：30마리의 흰쥐를 대상으로 경동맥 풍선 손상 3일 전부터 everolimus(everolimus군, N=15) 또는 위약(대조군, N=15)을 1.25 mg/kg 용량으로 매일 경구 투여하였다. Everolimus군과 대조군 동물들을 각각 1/3씩 나누어 혈관 손상 후 3일, 7일, 14일째 조직을 채취하여 치료효과를 판정하였다.
결 과：
혈관 손상 3일 후 everolimus군에서 외막세포 증식이 유의하게 감소하였으며 신내막 형성은 everolimus군에서 혈관 손상 7일 후(대조군 0.06±0.01 mm2, everolimus군 0.01±0.01 mm2, p<0.01) 및 14일 후(대조군 0.28±0.06 mm2, everolimus군 0.08±0.03 mm2, p<0.01) 유의하게 감소하였다.
결 론：
흰쥐의 경동맥 풍선 손상 모델에서 everolimus 경구투여는 외막세포의 활성화와 신내막 형성을 감소시킨다.

참고문헌 (Reference)

1 "Vascular myofibroblasts: lessons from coronary repair and remodeling" 17 : 417-422, 1997

2 "Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimuseluting stents in human coronary arteries" 107 : 381-383, 2003

3 "Transluminal dilatation of coronary-artery stenosis" 1 : 263-, 1978

4 "The effect of external beam radiation on neointimal formation in the rat carotid injury model" 28 : 173-182, 1998

5 "Systemic drug therapy for restenosis: "deja vu all over again"" 106 : 2296-2298, 2002

6 "Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model" 104 : 1188-1193, 2001

7 "Smooth muscle-specific SM22 protein is expressed in the adventitial cells of the balloon-injured rabbit carotid artery" 19 : 1393-1404, 1999

8 "Six- and twelve-month results from first human experience using everolimus-eluting stents with bioabsorbable polymer" 109 : 2168-2171, 2004

9 "SDZ RAD, a new rapamycin derivative: synergism with cyclosporine" 64 : 32-35, 1997

10 "Regulation and differentiation of vascular smooth muscle cells" 75 : 487-517, 1995

11 "Rapamycin inhibits vascular smooth muscle cell migration" 98 : 2277-2283, 1996

12 "Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury: its effect on cellular, growth factor, and cytokine response in injured vessels" 55 : 1409-1418, 1993

13 "Population pharmacokinetics of sirolimus in kidney transplant patients" 61 : 416-428, 1997

14 "Pilot trial of oral rapamycin for recalcitrant restenosis" 107 : 1722-1724, 2003

15 "Pathological analysis of local delivery of paclitaxel via a polymer-coated stent" 104 : 473-479, 2001

16 "Oral everolimus inhibits in-stent neointimal growth" 106 : 2379-2384, 2002

17 "Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model" 109 : 1558-1563, 2004

18 "Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin" 33 : 829-835, 1999

19 "Molecular and cellular phenotypes and their regulation in smooth muscle" 134 : 235-320, 1999

20 "Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious?" 109 : 701-705, 2004

21 "Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study" 103 : 192-195, 2001

22 "Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries" 93 : 2178-2187, 1996

23 "First clinical experience with a paclitaxel derivate-eluting polymerstent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome" 105 : 1883-1886, 2002

24 "Effect of paclitaxel local delivery on neointimal Formation after endothelial denudation of the rat carotid artery" 30 : 198-207, 2000

25 "Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model" 30 : 2200-2203, 1998

26 "Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries" 101 : 1362-1365, 2000

27 "Contribution of adventitial fibroblast to neointima formation and vascular remodeling: from innocent bystander to active participant" 89 : 1111-1121, 2001

28 "Atherosclerosis: the road ahead" 104 : 503-516, 2001

29 "Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis" 109 : 634-640, 2004

30 "Adventitial remodeling after coronary arterial injury" 93 : 340-348, 1996

31 "Adventitial myofibroblasts contribute to neointimal formation in porcine coronary arteries" 94 : 1655-1664, 1996

32 "Adventitial cells do not contribute to neointimal mass after balloon angioplasty of the rat common carotid artery" 104 : 1591-1593, 2001

33 "Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats" 27 : 627-632, 1999