BACKGROUND: Recent studies suggest that modulation of estrogen receptor β (ERβ) may play a crucial role in maintaining vascular homeostasis. We hypothesized that selective ERβ activation will attenuate atherogenesis via anti-inflammatory mechanisms. METHODS AND RESULTS: Atherosclerosis-prone apoE mice were ovariectomized and then fed a high-cholesterol diet with daily subcutaneous injections of the highly selective and potent ERβ agonist (8β-VE2) for 5 weeks. Compared with controls, treatment with 8β-VE2 reduced aortic arch atherosclerotic lesion areas by 34% of total and 75% of dense lesions, while not altering the serum lipid profile. We attribute these observed vascular effects solely to ERβ modulation as (1) treatment with the nonselective ER antagonist ICI 182,780 completely abrogated the beneficial vascular effects of 8β-VE2 and (2) uterine weight (a sensitive indicator of ERα modulation) did not change with 8β-VE2 treatment. Moreover, mice treated with 8β-VE2 had reduced serum interleukin 1β and tumor necrosis factor α levels. Finally, treatment of macrophages in vitro with 8β-VE2 blocked the uptake of acetylated low-density lipoprotein, suppressed the extracellular levels of the inflammatory cytokine tumor necrosis factor α, and enhanced the extracellular levels of the antiatherogenic/anti-inflammatory protein heat shock protein 27. CONCLUSIONS: Selective ERβ activation by 8β-VE2 attenuates atherogenesis and is associated with favorable modulation of vascular inflammation.
BACKGROUND: Recent studies suggest that modulation of estrogen receptor β (ERβ) may play a crucial role in maintaining vascular homeostasis. We hypothesized that selective ERβ activation will attenuate atherogenesis via anti-inflammatory mechanisms. METHODS AND RESULTS:Atherosclerosis-prone apoEmice were ovariectomized and then fed a high-cholesterol diet with daily subcutaneous injections of the highly selective and potent ERβ agonist (8β-VE2) for 5 weeks. Compared with controls, treatment with 8β-VE2 reduced aortic arch atherosclerotic lesion areas by 34% of total and 75% of dense lesions, while not altering the serum lipid profile. We attribute these observed vascular effects solely to ERβ modulation as (1) treatment with the nonselective ER antagonist ICI 182,780 completely abrogated the beneficial vascular effects of 8β-VE2 and (2) uterine weight (a sensitive indicator of ERα modulation) did not change with 8β-VE2 treatment. Moreover, mice treated with 8β-VE2 had reduced serum interleukin 1β and tumor necrosis factor α levels. Finally, treatment of macrophages in vitro with 8β-VE2 blocked the uptake of acetylated low-density lipoprotein, suppressed the extracellular levels of the inflammatory cytokine tumor necrosis factor α, and enhanced the extracellular levels of the antiatherogenic/anti-inflammatory protein heat shock protein 27. CONCLUSIONS: Selective ERβ activation by 8β-VE2 attenuates atherogenesis and is associated with favorable modulation of vascular inflammation.
Authors: Jinyou Liu; Suryavathi Viswanadhapalli; Lauren Garcia; Mei Zhou; Binoj C Nair; Edward Kost; Rajeshwar Rao Tekmal; Rong Li; Manjeet K Rao; Tyler Curiel; Ratna K Vadlamudi; Gangadhara R Sareddy Journal: Oncotarget Date: 2017-07-25
Authors: Veronika A Myasoedova; Tatyana V Kirichenko; Alexandra A Melnichenko; Varvara A Orekhova; Alessio Ravani; Paolo Poggio; Igor A Sobenin; Yuri V Bobryshev; Alexander N Orekhov Journal: Int J Mol Sci Date: 2016-08-11 Impact factor: 5.923