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

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-mediated androgen actions. Our aim was to determine the role of androgens in the sex differences in cardiac damage during myocardial infarction. Mature age-matched male and female Sprague Dawley rats, intact or surgically gonadectomized (Gx), received testosterone (T) or 17β-estradiol (E2) via subdermal SILASTIC (Dow Corning Corp.) implants; a subset of male rats received dihydrotestosterone. After 21 days, animals were anesthetized, and hearts were 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 (dihydrotestosterone, 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 up-regulated androgen receptor and receptor for advanced glycation end products, 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 myocardial infarction and shows that a novel mechanism of action for androgens during I-R is down-regulation of antiapoptotic protein Bcl-xL (B cell lymphoma-extra large), a key controller for cross talk between autophagy and apoptosis, shifting the balance toward apoptosis and leading to aggravated cardiac damage.

Cardiac effects of aldosterone: Does gender matter?

“…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].…”

“…We have recently identified key roles for sex steroids during MI, to regulate the balance between autophagy and apoptosis ( Fig. 1), with less cardiac damage in females due to reduced apoptosis and sustained autophagy [58]. These experimental studies are confirmed clinically, with higher apoptotic rate in the peri-infarct region of post-mortem hearts from men dying after acute MI than women [59].…”

“…Ovariectomy aggravates cardiac remodelling post-MI [56], whereas there is either no difference in infarct size or cardiac remodelling between males and females [57] or reduced infarct size post-MI for females [58]. We have recently identified key roles for sex steroids during MI, to regulate the balance between autophagy and apoptosis ( Fig.…”

“…Low circulating levels of testosterone in men are associated with poor outcomes in heart failure and decreased survival [60], however further controlled studies are required since conflicting reports continue. Similarly, there are only very few pre-clinical studies on the direct cardiac effects of testosterone in males and these are not consistent, with both detrimental and protective actions reported [58,61]. The effect of MR blockade to modulate testosterone's action was examined in vitro in cultured H9c2 cardiomyoblasts exposed to hyperosmotic stress with sorbitol [62].…”

“…The investigators concluded that testosterone may be protective during cardiomyocyte apoptosis and the beneficial actions of spironolactone in cardiomyocytes may be diminished by blockade of this protective action of testosterone. We recommend further studies are required since there was no doseresponse study or justification provided for the dose of testosterone selected (100 nM) and the pharmacological concentration of sorbitol (0.6 M), since circulating levels of testosterone are lower in healthy young (18-35 years) men, ranging from 8 to 28 nM [63], and $2.8 ng/ml in rodents [58]. In addition, the doses of spironolactone and eplerenone selected (10 lM) were not comparable to those used in clinical practice.…”