Sexually Dimorphic Relationships Among Saa3 (Serum Amyloid A3), Inflammation, and Cholesterol Metabolism Modulate Atherosclerosis in Mice

OBJECTIVE: Expression of the extrahepatic acute-phase protein serum amyloid A3 (Saa3) increases in response to acute and chronic inflammatory stimuli and is elevated in adipose tissue and macrophages in obese mice. A recent report suggested that Saa3 is pro-atherogenic in male ApoE(−/−) mice. Due to our previous observation that female but not male Saa3-deficient mice are protected from obesity, adipose inflammation, and hyperlipidemia, we sought to determine whether Saa3 differentially modulates atherosclerosis in mice of both sexes. APPROACH AND RESULTS: To promote atherosclerosis, Saa3(+/+) and Saa3(−/−) male and female mice were crossed with Ldlr(−/−) mice. All mice consumed a diet high in saturated fat and sucrose with 0.15% added cholesterol for 16 weeks. Plasma lipids and atherosclerosis levels were assessed. Female Saa3(−/−)Ldlr(−/−) mice exhibited elevated cholesterol levels relative to Saa3(+/+)Ldlr(−/−) controls, and exhibited increased atherosclerosis, while male Saa3(−/−)Ldlr(−/−) mice were protected from atherosclerosis. Data from the Hybrid Mouse Diversity Panel revealed that Saa3 associates strongly with inflammatory, Trem2-associated, and tissue remodeling genes and pathways in males but not females, an effect confirmed in liver tissue, atherosclerotic lesions, and cultured macrophages. Macrophages isolated from male and female mice showed differential inflammatory effects of Saa3 deficiency, an effect linked with sex steroid signaling. Cholesterol efflux capacity was increased in Saa3(−/−) males only. CONCLUSIONS: Saa3 is pro-atherogenic in male but atheroprotective in female mice, effects that may be related to sex-specific relationships between Saa3, cholesterol metabolism, inflammatory genes, and Trem2 macrophages

Postmenopausal Estrogen Therapy and Depressive Symptoms in Older Women

BACKGROUND: Evidence regarding the effect of postmenopausal estrogen therapy on mood is limited. METHODS: To determine whether postmenopausal estrogen therapy is associated with fewer depressive symptoms in elderly women, we conducted a cross-sectional study of 6,602 white women ages 71 years or older who were recruited from population-based listings in Baltimore, Md; Minneapolis, Minn; Portland, Ore; and the Monongahela Valley, Pa. Use of estrogen and progestin was determined by interview. Participants completed the Geriatric Depression Scale short form (GDS) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. RESULTS: A total of 6.3% (72/1,150) of current estrogen users, 7.2% (142/1,964) of past estrogen users, and 9.0% (313/3,488) of never users reported 6 or more symptoms of depression (P = .004). Current estrogen users had a decreased risk of reporting 6 or more depressive symptoms, compared with not current (past or never) users of estrogen (odds ratio [OR], 0.7; 95% CI, 0.5 to 0.9; P = .01], adjusted for living alone, bilateral oophorectomy, current smoking, physical activity, social network, self-perceived health, cognitive function, functional status, and antidepressant use. However, excluding women who use estrogen or progestin alone, we were unable to find an association between current use of combined estrogen plus progestin therapy and depressive symptoms (adjusted OR, 0.8; 95% CI, 0.5 to 1.4; P = .5). CONCLUSIONS: This cross-sectional study found that current use of unopposed estrogen was associated with a decreased risk of depressive symptoms in older women. Additional studies are needed to understand the effect of combined estrogen and progestin therapy on the prevalence of depressive symptoms in older women