TY - JOUR
T1 - 17β-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function
T2 - A preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutation
AU - Chen, Youzhou
AU - Zhang, Zhuoli
AU - Hu, Fenghuan
AU - Yang, Weixian
AU - Yuan, Jiansong
AU - Cui, Jingang
AU - Hao, Shujing
AU - Hu, Jie
AU - Zhou, Ying
AU - Qiao, Shubin
N1 - Funding Information:
All authors had final approval of the submitted and published versions. This work was partially supported by the National Science Foundation of China (81370327)
Publisher Copyright:
©2014 Elsevier Ltd. All rights reserved.
PY - 2015/3
Y1 - 2015/3
N2 - 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.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.
AB - 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.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.
KW - Energy metabolism
KW - Estrogen replacement
KW - Hypertrophic cardiomyopathy
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U2 - 10.1016/j.jsbmb.2014.12.011
DO - 10.1016/j.jsbmb.2014.12.011
M3 - Article
C2 - 25541436
AN - SCOPUS:84920169941
VL - 147
SP - 92
EP - 102
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
ER -