Combination of raloxifene, aspirin and estrogen as novel paradigm of hormone replacement therapy in rabbit model of menopause.

AIM: To assess a novel hormone replacement therapy (HRT) paradigm using raloxifene, aspirin combined with estrogen in rabbit model of menopause. METHODS: Female New Zealand white rabbits were ovariectomized or sham-operated. The ovariectomized rabbits were divided into 7 groups: estradiol valerate (E(2)), raloxifene, aspirin, E(2) /raloxifene, E(2)/aspirin, E(2) /raloxifene/aspirin and vehicle. Two weeks after the operation, the rabbits were administered the above drugs for 12 weeks. Then, the mammary glands were examined histologically, uterus was weighted, and blood sample was collected for analyzing the levels of estrogen, serum lipids and monocyte chemoattractant protein (MCP)-1, and platelet aggregation. The aortic tissue was examined morphometrically. RESULTS: Compared with E(2) 0.1 mg·kg(-1)·d(-1) treatment alone, the pairing of raloxifene 10 mg·kg(-1)·d(-1) with E(2) significantly decreased the extent of mammary gland branches and ducts (5.53%±1.23% vs 15.4%±2.17%, P<0.01), as well as the uterine weight (2.16±0.35 g vs 4.91±0.75 g, P<0.01). However, E(2)/raloxifene or E(2) alone treatment significantly stimulated platelet aggregation relative to vehicle group. Addition of aspirin 5 mg·kg(-1)·d(-1) reduced platelet aggregation to almost the same level as the vehicle group. E(2) treatment exerted a positive effect on serum lipids and MCP-1, and a regression in aortic intimal plaque size compared to the vehicle. Raloxifene reinforced the positive effects of E(2). CONCLUSION: The combination of raloxifene, aspirin and E(2) exhibits positive lipid, MCP-1 and atherosclerotic responses with minimal stimulation of breast and uterine tissues as well as platelet aggregation in a rabbit model of the menopause.

Peroxisome proliferator-activated receptor-gamma1 gene therapy attenuates atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice.

Peroxisome proliferator-activated receptor-gamma1 (PPARgamma1) is an important transcription factor involved in atherosclerosis progression. Thus, PPARgamma1 appears to be an interesting gene therapeutic target to favorably affect atherosclerosis development. The present study was carried out to test the hypothesis that PPARgamma1 gene therapy may attenuate and stabilize atherosclerotic plaques in apolipoprotein E-knockout mice. The recombinant adenovirus carrying mouse PPARgamma1 cDNA (AdPPARgamma1) was constructed and AdPPARgamma1 (5 x 10(8) PFU) or AdGFP (5 x 10(8) PFU), diluted to a total volume of 200 mul, was injected into the tail vein of mice (40 weeks of age and fed a high-fat diet) in two intervention groups (n = 20 each). Mice (n = 20) injected with phosphate-buffered saline (PBS) served as vehicle controls. The results showed that 4-week treatment with AdPPARgamma1 attenuated atherosclerotic lesions, although the overall mRNA levels of CD36 were increased in the AdPPARgamma1 group. Moreover, PPARgamma1 gene overexpression stabilized atherosclerotic plaques as shown by the reduced depositions of lipids and macrophages and increased contents of smooth muscle cells and collagen within the plaques. In addition, marked upregulation of the mRNA levels of cholesterol efflux-related molecules such as liver X receptor alpha and ATP-binding cassette transporter A1 in liver, and downregulation of matrix metalloproteinase-9, human tissue factor, CD40, CD40 ligand, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, macrosialin, class A scavenger receptor, and macrophage migration inhibitory factor in aorta, were demonstrated in AdPPARgamma1-treated animals. In contrast, there was no significant difference in aforementioned parameters between the AdGFP and PBS groups. In conclusion, overexpression of the PPARgamma1 gene exerts beneficial effects in attenuating atherosclerosis progression and stabilizes vulnerable plaques. Thus, PPARgamma1 might offer a promising gene therapeutic target against atherosclerosis.

Effects of raloxifene on caveolin-1 mRNA and protein expressions in vascular smooth muscle cells.

Caveolin-1 is regulated by estrogen in vascular smooth muscle cells. Raloxifene, a selective estrogen receptor modulator that possibly has cardioprotective properties without an increased risk of cancer or other side effects of estrogen, may be used in women with risk of coronary artery disease. However, the relationship between raloxifene and caveolin-1 is still unknown. Therefore, this study was designed to see whether raloxifene regulates caveolin-1 expression and if so, whether such regulation is mediated by estrogen receptor. Rat aortic smooth muscle cells were cultured in the absence or presence of raloxifene (10(8-) to 10(6-) M) for 12 or 24 h. Both mRNA and protein levels of caveolin-1 were increased significantly after 24 h treatment with raloxifene. These increases were inhibited by estrogen receptor antagonist ICI 182780 (10(5-) M). Results of this study suggest that raloxifene stimulates caveolin-1 transcription and translation through estrogen receptor mediated mechanisms.