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Uncovering sex-specific mechanisms of action of testosterone and redox balance.

ABSTRACT: The molecular and pharmacological manipulation of the endogenous redox system is a promising therapy to limit myocardial damage after a heart attack; however, antioxidant therapies have failed to fully establish their cardioprotective effects, suggesting that additional factors, including antioxidant system interactions with other molecular pathways, may alter the pharmacological effects of antioxidants. Since gender differences in cardiovascular disease (CVD) are prevalent, and sex is an essential determinant of the response to oxidative stress, it is of particular interest to understand the effects of sex hormone signaling on the activity and expression of cellular antioxidants and the pharmacological actions of antioxidant therapies. In the present review, we briefly summarize the current understanding of testosterone effects on the modulation of the endogenous antioxidant systems in the CV system, cardiomyocytes, and the heart. We also review the latest research on redox balance and sexual dimorphism, with particular emphasis on the role of the natural antioxidant system glutathione (GSH) in the context of myocardial infarction, and the pro- and antioxidant effects of testosterone signaling via the androgen receptor (AR) on the heart. Finally, we discuss future perspectives regarding the potential of using combing antioxidant and testosterone replacement therapies to protect the aging myocardium.

SUBMITTER: Cruz-Topete D

PROVIDER: S-EPMC7212492 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Uncovering sex-specific mechanisms of action of testosterone and redox balance.

Cruz-Topete Diana D Dominic Paari P Stokes Karen Y KY

Redox biology 20200305

The molecular and pharmacological manipulation of the endogenous redox system is a promising therapy to limit myocardial damage after a heart attack; however, antioxidant therapies have failed to fully establish their cardioprotective effects, suggesting that additional factors, including antioxidant system interactions with other molecular pathways, may alter the pharmacological effects of antioxidants. Since gender differences in cardiovascular disease (CVD) are prevalent, and sex is an essent ...[more]

PMID: 32169396

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Project description:BackgroundPrevious studies have suggested associations between testosterone, genetic factors, and a series of complex diseases, but the associations with the lifespan phenotype, such as health span, remain unclear.MethodsIn this prospective cohort study, we analyzed 145,481 men and 147,733 women aged 38-73 years old from UK Biobank (UKB) to investigate the sex-specific associations of total testosterone (TT), free testosterone (FT), or polygenic risk score (PRS) with health span termination (HST) risk. At baseline, serum testosterone levels were measured. HST was defined by eight events strongly associated with longevity. PRS, an efficient tool combining the effect of common genetic variants to discriminate genetic risk of complex phenotypes, was constructed by 12 single-nucleotide polymorphisms related to health span from UKB (P ≤ 5.0 × 10-8). We used multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsWith a median follow-up time of 7.70 years, 26,748 (18.39%) men and 18,963 (12.84%) women had HST. TT was negatively associated with HST in men [HR per standard deviation (SD) increment of log-TT: 0.92, 95% CI: 0.88-0.97]. Inversely, both TT (HR per SD increment of log-TT: 1.05, 95% CI: 1.02-1.08) and FT (HR per SD increment of log-FT: 1.08, 95% CI: 1.05-1.11) presented an increased risk of HST in women. PRS was positively associated with HST risk (quintile 5 versus quintile 1, men, HR: 1.19, 95% CI: 1.15-1.24; women, HR: 1.21, 95% CI: 1.16-1.27). Moreover, men with high TT and low genetic risk showed the lowest HST risk (HR: 0.80, 95% CI: 0.73-0.88), whereas HST risk for women with both high TT and genetic risk increased obviously (HR: 1.32, 95% CI: 1.19-1.46). Similar joint effects were observed for FT in both genders.ConclusionsWe observed sex-specific associations that testosterone was negatively associated with HST risk in men and positively associated with HST risk in women. Genetic factors increased the HST risk, suggesting that participants with both high genetic risk and abnormal testosterone levels (high level in women or low level in men) should be the target for early intervention. Although our findings highlight the associations between testosterone and health span, further mechanistic studies and prospective trials are warranted to explore the causation behind.

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Uncovering sex-specific mechanisms of action of testosterone and redox balance.

Publications

Uncovering sex-specific mechanisms of action of testosterone and redox balance.

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