Sex-related differences in cardiac function have been well documented. The extent to which sex hormones are responsible for these differences is unclear. The current study was designed to determine whether castration and androgen replacement resulted in changes in functional expression of genes encoding the L-type calcium channel and Na/Ca exchanger in isolated rat ventricular myocytes. Sixteen weeks of castration produced a 50% decline in dihydropyridine receptor expression levels and a 16% (P < 0.05) increase in time to peak shortening. Furthermore, cardiac myocytes isolated from castrated animals also displayed an 18% (P < 0.001) increase in time to relengthening and an 80% decrease in Na/Ca exchanger gene expression when compared with intact controls. Testosterone treatment of castrated animals completely reversed these effects. These results provide the first evidence that androgens regulate functional expression of the L-type calcium channel and the Na/Ca exchanger in isolated rat ventricular myocytes and thus may play a role in modulating cardiac performance in males and thereby contribute to the observed gender differences in cardiac function.
A critical problem within transcription factor families is how diverse regulatory programs are directed by highly related members. Androgen and glucocorticoid receptors (AR, GR) recognize a consensus DNA hormone response element (HRE), but they activate target genes with precise specificity, largely dependent on the promoter and cell context. We have assessed the role of different receptor domains in hormone-specific response by testing chimeras of AR and GR for their ability to activate the androgen-specific enhancer of the mouse sex-limited protein (Slp) gene. Although all of the mutant receptors activated simple HREs, only a few activated the androgen-specific element. One component shared by receptors functional on the AR-specific target was the AR DNA binding domain. Activation was not due to differential DNA affinity but rather to the AR DNA binding domain escaping suppression directed at the GR DNA binding domain in this enhancer context. A further mechanism increasing specific activation was cooperation of receptors at multiple and weak HREs, which was accentuated in the presence of both the AR N terminus and ligand binding domain. These domains together increased recognition of weak HREs, as demonstrated by in vitro DNase I footprinting and transactivation of mutant enhancers. Further, AR N-terminal subdomains reported to interact directly with the ligand binding domain relieved an inhibitory effect imposed by that domain. Therefore, functions intrinsic to AR augment steroid-specific gene activation, by evading negative regulation operating on the domains of other receptors and by enhancing cooperativity through intra-and inter-receptor domain interactions. These subtle distinctions in AR and GR behavior enforce transcriptional specificity established by the context of nonreceptor factors.
Sex-related differences in the cardiac phenotype have been well established. This study was designed to determine whether androgens regulate myocardial gene expression and play a role in the sex-related differences in the myocardial phenotype. Gonadectomized male rats were treated with testosterone, and myocardial gene expression was examined in whole heart using quantitative real-time PCR. Gonadectomy produced a substantial decrease in mRNA levels for the androgen receptor, Na(+)/Ca(2+) exchanger, L- type calcium channel, and beta(1)-adrenergic receptor (beta(1)AR). Supplementation of testosterone in castrates produced a fivefold increase in androgen receptor mRNA levels. Testosterone treatment of castrates produced almost a sixfold increase in Na(+)/Ca(2+) exchanger mRNA, a tenfold increase in Ltype calcium channel mRNA accumulation, and a fourfold increase in beta(1)AR mRNA levels. Increased calcium channel expression, beta(1)AR expression, and Na(+)/Ca(2+) exchanger expression together may alter cytosolic calcium. These results provide the first evidence that testosterone regulates expression of myocardial calcium regulating genes and thus may play a role in modulating the cardiac phenotype in males.
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