Although recent clinical trials have found an increased incidence of
cardiovascular disease in women on
estrogen replacement therapy, the underlying mechanism remains unclear. We have recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl
salt-sensitive and Zucker rats, as a new animal model of
metabolic syndrome. We have now examined the effects of
estrogen replacement on cardiac pathophysiology in ovariectomized female DS/obese (Ovx-DS/obese) rats. Animals subjected to
ovariectomy at 7 weeks of age were implanted subcutaneously with a 60-day release pellet containing 0.5 mg of 17β-estradiol (E(2)) or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Lepr(+)/Lepr(+) or DS/lean rats) of DS/obese rats served as controls. Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 13 weeks of age. Ovx-DS/obese rats manifested
hypertension at 7 weeks of age and thereafter and showed left ventricular (LV)
fibrosis and diastolic dysfunction at 13 weeks. Treatment with E(2) attenuated
hypertension in Ovx-DS/obese rats but had no effect on blood pressure in ovariectomized female DS/lean (Ovx-DS/lean) rats. E(2) treatment exacerbated LV
fibrosis and diastolic dysfunction, as well as further increased cardiac oxidative stress and
inflammation in Ovx-DS/obese rats, and it elicited similar effects in Ovx-DS/lean rats. E(2) reduced food intake,
body weight, and visceral fat content in both Ovx-DS/obese and Ovx-DS/lean rats. E(2) treatment attenuated
hypertension and
obesity but exacerbated LV
fibrosis and diastolic dysfunction in Ovx-DS/obese rats, with these latter effects being associated with increased cardiac oxidative stress and
inflammation.