Estrogen deprivation aggravates cardiometabolic dysfunction in obese-insulin resistant rats through the impairment of cardiac mitochondrial dynamics

Abstract

The incidence of cardiovascular disease and metabolic syndrome increases after the onset of menopause, suggesting estrogen has a vital role in their prevention. Mitochondrial dynamics are known to play an important role in the maintenance of cardiac physiological function. However, the effects of estrogen deprivation on cardiometabolic status and cardiac mitochondrial dynamics under conditions of obese-insulin resistance have never been investigated. We hypothesized that estrogen deprivation aggravates cardiac dysfunction through increased cardiac mitochondrial fission in obese-insulin resistant rats. Female rats were fed on either a high fat (HFD, 57.60% fat) or normal (ND, 19.77% fat) diet for 13 weeks. The rats were then divided into 4 groups. Two sham groups (HFS and NDS) and 2 operated or ovariectomized (HFO and NDO) groups (n = 8/group). Six weeks after surgery, metabolic status, heart rate variability (HRV), left ventricular (LV) function, cardiac mitochondrial function and dynamics, and metabolic parameters were determined. Insulin resistance developed in NDO, HFS and HFO rats as indicated by increased plasma insulin and HOMA index. Although rats in both NDO and HFS groups had markedly impaired LV function indicated by reduced %LVFS and impaired cardiac mitochondrial function, rats in the HFO group had the most severe impairments. Moreover, the estrogen deprived rats (NDO and HFO) had increased cardiac mitochondrial fission through activation of phosphorylation of Drp-1 at serine 616. Our findings indicated that estrogen deprivation caused the worsening of LV dysfunction through increased cardiac mitochondrial fission in obese-insulin resistant rats.