title: 17β-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function: a preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutation.
abstract: OBJECTIVE
  We investigated the effect of ovariectomy (OVX) and 17β-estradiol (E2) replacement on both mitochondrial and myocardial function in cTnT-Q92 transgenic mice generated by cardiac-restricted expression of a human hypertrophic cardiomyopathy (HCM) mutation.
  
  
  METHODS
  The cTnT-Q92 mice were ovariectomized at twenty weeks of age and were treated with either placebo (OVX group) or E2 (OVX+E2 group) for twelve weeks before being sacrificed. Wild-type and cTnT-Q92 female mice receiving sham operation were used as controls. Indices of diastolic function such as mitral early (E) and late (A) inflow as well as isovolumic relaxation time (IVRT) were measured by echocardiography. A Clark-type electrode was used to detect respiratory control, and ATP levels were determined at the mitochondrial level using HPLC. Key components related to mitochondrial energy metabolism, such as peroxisome proliferator-activated receptor α (PPARα), PPARγ coactivator 1α (PGC-1α) and nuclear respiratory factor-1 (NRF-1), were also analyzed using Western blot and RT-PCR. The levels of oxidative stress markers were determined by measuring malondialdehyde (MDA) using the thiobarbituric acid assay.
  
  
  RESULTS
  The cTnT-Q92 mice had impaired diastolic function compared with wild-type mice (E/A ratio, 1.39 ± 0.04 vs. 1.21 ± 0.01, p<0.001; IVRT, 19.17 ± 0.85 vs. 22.15 ± 1.43 ms, p=0.028). In response to ovariectomy, cardiac function further decreased compared with that observed in cTnT-Q92 mice that received the sham operation (E/A ratio, 1.15 ± 0.04 vs. 1.21 ± 0.01, p<0.001; IVRT, 28.31 ± 0.39 vs. 22.15 ± 1.43 ms, p=0.002). Myocardial energy metabolism, as determined by ATP levels (3.49 ± 0.31 vs. 5.07 ± 0.47 μmol/g, p<0.001), and the mitochondrial respiratory ratio (2.04 ± 0.10 vs. 2.63 ± 0.11, p=0.01) also decreased significantly. By contrast, myocardial concentrations of MDA increased significantly in the OVX group, and PGC-1α, PPARα and NRF-1decreased significantly. E2 supplementation significantly elevated myocardial ATP levels (4.55 ± 0.21 vs. 3.49 ± 0.31 μmol/g, p=0.003) and mitochondrial respiratory function (3.93 ± 0.05 vs. 2.63 ± 0.11, p=0.001); however, it reduced the MDA level (0.21 ± 0.02 vs. 0.36 ± 0.03 nmol/g, p<0.001), which subsequently improved diastolic function (E/A ratio, 1.35 ± 0.06 vs. 1.15 ± 0.04, p<0.001; IVRT, 18.22 ± 1.16 vs. 28.31 ± 0.39 ms, p=0.007).
  
  
  CONCLUSIONS
  Our study has shown that 17β-estradiol improved myocardial diastolic function, prevented myocardial energy dysregulation, and reduced myocardial oxidative stress in cTnT-Q92 mice.
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
authors.forename: Youzhou
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 737 N Michigan Ave., 16th Floor, Chicago, USA.
authors.forename: Zhuoli
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
authors.forename: Fenghuan
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
authors.forename: Weixian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
authors.forename: Jingang
authors.initials: J
authors.lastname: Cui
authors.affiliation: Clinical Laboratory of Zhongke, Beijing, China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Hao
authors.affiliation: Clinical Laboratory of Zhongke, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, China. Electronic address: qsbfw@sina.com.
authors.forename: Shubin
authors.initials: S
authors.lastname: Qiao
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha; D020107:Troponin T / Q000235:genetics*
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D020107:Troponin T; D004958:Estradiol
keywords: Energy metabolism; Estrogen replacement; Hypertrophic cardiomyopathy