Doctoral Theses from Sahlgrenska Academy

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Browsing Doctoral Theses from Sahlgrenska Academy by Subject "2-methoxyestradiol"

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    Actions of androgens and estrogens in experimental models of cardiovascular disease
    (2010-10-31) Bourghardt, Johan
    Men are at higher risk of developing both atherosclerotic cardiovascular disease and abdominal aortic aneurysm (AAA). Actions of sex steroids are hypothesized to underlie these gender differences. Testosterone, the major androgen, reduces atherosclerosis in male animal models but is suggested to promote AAA formation. However, the role of the androgen receptor (AR) in mediating these effects of androgens is unknown. Further, the physiological metabolic actions of androgens in females are unclear. Estradiol, the major estrogen in females, reduces atherosclerosis in female animal models and can be metabolized to 2-methoxyestradiol, a biologically active metabolite, in the vascular wall. This thesis aimed 1) to determine the role of the AR in the atheroprotection by testosterone in male mice, and 2) to investigate the physiological, AR-dependent actions of androgens in the development of atherosclerosis in female mice, and 3) to investigate the role of the AR in the development of AAA in male mice, and 4) to examine whether 2-methoxyestradiol affects the development of atherosclerosis in female mice. Male and female AR-deficient mice (AR- and AR-/-) on apolipoprotein E-deficient background were generated using Cre/loxP technology. Male AR- mice fed a high-fat diet displayed accelerated atherosclerosis and reduced atheroprotection by testosterone. Female AR-/- mice fed a high-fat diet displayed accelerated atherosclerosis associated with several features of the metabolic syndrome including obesity, insulin resistance and dyslipidemia. In an angiotensin II-induced model of AAA formation, male AR- mice were protected from the development of AAA while displaying increased atherosclerosis, and testosterone increased AAA formation in controls, but not in AR- mice. In addition, 2-methoxyestradiol treatment reduced atherosclerotic lesion formation in female apolipoprotein E-deficient mice. In conclusion, AR-mediated actions of androgens play important roles in both male and female mice. In males, AR-mediated actions of testosterone reduce atherosclerosis and promote AAA formation. In females, AR-mediated effects of androgens are important for metabolism and protects against atherosclerosis. Further, the estradiol metabolite 2-metoxyestradiol may hold promise as an atheroprotective drug.
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    Estrogen and 2-methoxyestradiol: regulation of arthritis, inflammation and reactive oxygen species
    (2014-04-25) Stubelius, Alexandra
    Rheumatoid arthritis (RA) is characterized by severe synovial inflammation, cartilage destruction, and immune-mediated bone loss. Estrogen ameliorates experimental RA, reducing both inflammation and bone loss. The inflamed tissues are damaged partly by innate immune cells producing reactive oxygen species (ROS). ROS can also regulate the immune system. This thesis aimed to investigate the regulation of inflammation and joint destruction by 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2me2). E2's and 2me2's immunomodulation were investigated both in experimental arthritis and in an unprovoked immune system. Both wild type (WT) mice and Catechol-O-methyltransferase (COMT)-deficient mice were used, as COMT metabolizes E2 into 2me2. Further, E2's regulatory role was investigated in WT mice or ROS-deficient mice (B10.Q.Ncf1*/*), in a model of osteoporosis and a local (LPS-induced) inflammation model. 2me2 ameliorated arthritis and bone mineral density (BMD), and regulated immune cells differently compared with E2. Treatment with high doses of 2me2 increased uteri weight, implying estrogen-receptor activation; 2me2 activated estrogen-response elements in a tissue-, and dose-dependent manner. Deficiency in the COMT enzyme only moderately affected the immune system, and males were more affected than females. In ovx-induced bone loss, ROS-deficient mice displayed reduced osteoclastogenesis compared to controls, but similar bone mineral density and immunological profiles. In LPS-induced inflammation, E2 treatment in WT mice shifted neutrophil infiltration to macrophage infiltration, while in ROS-deficient mice E2 treatment induced neutrophil infiltration and reduced the macrophages. In conclusion, E2's metabolite 2me2 can modulate arthritis and inflammation-triggered osteoporosis. At high doses 2me2 can induce estrogen receptor signaling. E2 together with ROS regulate inflammation and osteoclastogenesis. Understanding estrogenic cellular and molecular mechanisms are important for developing new arthritis and inflammationtreatments. Our results increase the understanding of estrogens' role in inflammation and motivate further investigations.