期刊
JOURNAL OF THE ENDOCRINE SOCIETY
卷 6, 期 11, 页码 -出版社
ENDOCRINE SOC
DOI: 10.1210/jendso/bvac132
关键词
castration; mice; heart; metabolism
资金
- Swedish Research Council [2017-02141]
- Swedish Heart-Lung Foundation [20180564]
- Novo Nordisk Foundation [NNF18OC0034464]
- Swedish government ((the ALF-agreement) [ALFGBG-721451]
- Swedish county councils (the ALF-agreement) [ALFGBG-721451]
- Netherlands Cardiovascular Research Initiative
- Dutch Heart Foundation [CVON2017-20]
- Leiden University Medical Center (LUMC)
- Formas [2017-02141] Funding Source: Formas
- Swedish Research Council [2017-02141] Funding Source: Swedish Research Council
Androgen deprivation therapy for prostate cancer, which reduces serum testosterone levels, is associated with increased risk of heart failure. This study found that castration in male mice alters cardiac energy substrate uptake, leading to metabolic remodeling and increased expression of fetal genes in the heart. Castration also resulted in reduced cardiac performance during pharmacological stress.
Androgen deprivation therapy of prostate cancer, which suppresses serum testosterone to castrate levels, is associated with increased risk of heart failure. Here we tested the hypothesis that castration alters cardiac energy substrate uptake, which is tightly coupled to the regulation of cardiac structure and function. Short-term (3-4 weeks) surgical castration of male mice reduced the relative heart weight. While castration did not affect cardiac function in unstressed conditions, we observed reductions in heart rate, stroke volume, cardiac output, and cardiac index during pharmacological stress with dobutamine in castrated vs sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids toward glucose, while testosterone replacement had the opposite effect. There was increased expression of fetal genes in the heart of castrated mice, including a strong increase in messenger RNA and protein levels of beta-myosin heavy chain (MHC), the fetal isoform of MHC. In conclusion, castration of male mice induces metabolic remodeling and expression of the fetal gene program in the heart, in association with a reduced cardiac performance during pharmacological stress. These findings may be relevant for the selection of treatment strategies for heart failure in the setting of testosterone deficiency.
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