Article

Role of Androgens in Sex Differences in Cardiac Damage During Myocardial Infarction

University of Sydney, Sydney, New South Wales, Australia
Endocrinology (Impact Factor: 4.64). 12/2013; 155(2):en20131755. DOI: 10.1210/en.2013-1755
Source: PubMed

ABSTRACT Age-specific incidence of ischemic heart disease in men is higher than in women, although women die more frequently without previous symptoms; the molecular mechanism(s) are poorly understood. Most studies focus on protection by estrogen, with less attention on androgen receptor (AR) mediated androgen actions. Our aim was to determine the role of androgens in the sex differences in cardiac damage during myocardial infarction (MI). Mature age-matched male and female Sprague Dawley rats - intact or surgically gonadectomized (Gx) - received testosterone (T) or estradiol (E2) via subdermal silastic implants; a subset of male rats received dihydrotestosterone (DHT). After 21 days, animals were anesthetized, hearts excised and subjected to ex vivo regional ischemia-reperfusion (I-R). Hearts from intact males had larger infarcts than those from females following I-R; Gx produced the opposite effect, confirming a role for sex steroids. In Gx males, androgens (DHT, T) and E2 aggravated I-R induced cardiac damage, whereas in Gx females, T had no effect and E2 reduced infarct area. Increased circulating T levels upregulated AR and receptor for advanced glycation end products (RAGE), which resulted in enhanced apoptosis aggravating cardiac damage in both males and females. In conclusion, our study demonstrates for the first time that sex steroids regulate autophagy during MI, and shows that a novel mechanism of action for androgens during I-R is downregulation of antiapoptotic protein Bcl-xL, a key controller for crosstalk between autophagy and apoptosis, shifting the balance towards apoptosis and leading to aggravated cardiac damage.

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    • "Differential regulation of these receptors may differ between males and females and whether there is cross-reactivity should also be considered. In recent studies , we did not find any differences in protein levels of AR, ER-a and ER-b, between male and female rats [58], in agreement with previous reports [70] [75]. In contrast, sex differences in MR mRNA levels have been reported in rat brain, while treatment with estrogen decreased MR mRNA expression and binding in the hippocampus [66]. "
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