長期給予雌性素受體調節劑raloxifene改善雌性素不足造成之血管基質金屬蛋白酶活性異常

Effects of Long-Term Treatment with Raloxifene, a Selective Estrogen Receptor Modulator, on Changes of Vascular Matrix Metalloproteinase-2 Activity Induced by Estrogen Deficiency

背景與目的：Raloxifene(RAL)為選擇性雌性素接受體調節劑(selective estrogen receptor modulators, SERMs)，具有雌性素受體致效或拮抗的雙重作用，其中在骨骼產生受體致效作用，而在乳房及子宮內膜皆是拮抗作用，目前為停經後婦女預防骨質疏鬆症。本實驗室過去發現estrogen可以改善血管之基質金屬蛋白酶-2(matrixmetalloproteinase-2;MMP-2)活性，使collagen不會過度累積而影響血管功能。本研究進一步觀察慢性RAL治療是否可以改善雌性素不足造成之血管舒張功能不良，並且避免MMP-2活性降低而造成血管collagen堆積。方法：本實驗將八週大之雌性大白鼠分成下列六組：(1)假手術組(sham)：大白鼠接受假手術；(2)卵巢切除組(Ovx)：將大白鼠兩側卵巢切除；(3)Ovx+RAL：將大白鼠兩側卵巢切除，經過一星期E2排空期後，每天經由胃管灌食RAL0.1、1或10mg/kg，分別給予四週；(4)Ovx+E2：將大白鼠兩側卵巢切除，經過一星期雌性素排空期後，每天經由皮下注射17β-estradiol(E2)50μg/kg，注射四週。利用尾部脈波描記法(tail-cuffmethod)，測量清醒動物的平均血壓；利用MultiWireMyographsystem測量腸繫膜動脈血管活性反應。結果：Ovx五週後平均尾動脈壓即明顯的上升，慢性補充RAL1及10mg/kg四週後可顯著的降低Ovx鼠之血壓。慢性補充RAL及E2四週之腸系膜血管對於ACh10-6M引起之舒張反應明顯優於Ovx組。Ovx五週後activeMMP-2蛋白質表現明顯減少，造成血管壁中collagentypeI堆積，慢性補充RAL0.1及1mg/kg可以改善上述現象。結論：長期補充適當劑量RAL後可改善大鼠因E2缺乏導致MMP-2活性降低的現象，進而減少血管中的collagen沈積，進一步預防血管重塑現象，藉此具有心臟血管保護作用。

Raloxifene(RAL), a selective estrogen receptor modulator (SERM), exerts estrogenagonistic effects on bone and estrogen-antagonistic effects on uterine endometrium and breast tissue. Hypertension is associated with increased peripheral vascular resistance and increase vascular remodeling in media/lumen ratio. The main feature of large artery remodeling is wall hypertrophy, due to change in smooth muscle cells and extracellular matrix(ECM) components. The ECM, mainly formed by collagen type Ι is very stiff protein and has the role to limit vessel distension. MMPs are a family of zinc- and calcium-dependent enzymes that are important in the degradation of ECM. Among the MMPs, gelatinase A(MMP-2) can degrade collagen, basement membrane and are believe to promote smooth muscle cell migration and proliferation which is important in arterial compliance and intimal thickening. In this study, we investigate whether longterm treatment with RAL can improve ovariectomy(Ovx)-induced reduction in MMP-2 activity and avoid vascular remodeling. Rats were divided into six groups: (1) sham: the rats were shamoperated; (2) Ovx: the rats were ovariectomized bilaterally; (3) Ovx + RAL 0.1: Ovx rats were given RAL (0.1 mg/kg, once/day, oral) for 4 weeks beginning 1 week after Ovx. (4) Ovx + RAL 1: Ovx rats were given RAL (1 mg/kg, once/day, oral) for 4 weeks beginning 1 week after Ovx. (5) Ovx rats were given RAL (10 mg/kg, once/day, oral) for 4 weeks beginning 1 week after Ovx; (6) OVX + E2: Ovx rats were given E2 (50 μg/kg, 3 times per week, s.c.) for 4 weeks beginning 1 week after OVX. Results demonstrated that mean blood pressure significantly increased 5 weeks after Ovx in conscious rats by tail cuff method, which was recovered by long-term treatment with RAL and E2. The vasodilator response of mesenteric artery to ACh (10-6 M) in RALtreated group was significantly greater than that of Ovx group. RAL 0.1 or 1 mg/kg for 4 weeks significantly improved the active MMP-2 expression which was markedly reduced by Ovx, and attenuated collagen type Ι deposition after Ovx. In conclusion, long-term treatment with RAL can improve vascular function and MMP-2 activity to reduce collagen deposition, by which vascular remodeling reduced and may participate to prevent hypertension.