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17β-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function: a preclinical study in a
Youzhou Chen1, Zhuoli Zhang2, Fenghuan Hu1
1Department 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.
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.
Insights
Ovariectomy worsened diastolic dysfunction and mitochondrial energy metabolism in hypertrophic cardiomyopathy mice. Estradiol (E2) replacement improved cardiac function, energy levels, and reduced oxidative stress in these mice.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Endocrinology
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart disease often associated with mutations in cardiac troponin T (cTnT).
- Ovariectomy (OVX) in female mammals leads to estrogen deficiency, potentially impacting cardiac health.
- Mitochondrial dysfunction and oxidative stress are implicated in the progression of cardiovascular diseases.
Purpose of the Study:
- To investigate the impact of ovariectomy (OVX) and 17β-estradiol (E2) replacement on mitochondrial and myocardial function in cTnT-Q92 transgenic mice modeling HCM.
- To assess the effects of estrogen deficiency and replacement on diastolic function, energy metabolism, and oxidative stress in the context of HCM.
Main Methods:
- cTnT-Q92 transgenic mice and wild-type littermates underwent OVX or sham surgery, followed by placebo or E2 treatment.
- Echocardiography was used to evaluate diastolic function (E/A ratio, IVRT).
- Mitochondrial function (respiratory control, ATP levels), energy metabolism markers (PPARα, PGC-1α, NRF-1), and oxidative stress (MDA) were assessed.
Main Results:
- cTnT-Q92 mice exhibited impaired diastolic function, which was further exacerbated by OVX, alongside decreased ATP levels and mitochondrial respiratory function.
- OVX led to increased myocardial oxidative stress (MDA) and reduced expression of key metabolic regulators (PGC-1α, PPARα, NRF-1).
- E2 supplementation significantly improved diastolic function, restored myocardial ATP levels and mitochondrial respiration, and reduced oxidative stress markers.
Conclusions:
- Estrogen deficiency, induced by OVX, exacerbates cardiac dysfunction and mitochondrial impairment in a mouse model of HCM.
- 17β-estradiol replacement therapy effectively ameliorates diastolic dysfunction, improves myocardial energy metabolism, and reduces oxidative stress in these mice.
- These findings highlight the cardioprotective role of estrogen and suggest potential therapeutic strategies for estrogen-deficient individuals with HCM.
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