Editorial: Cardiac steroidogenesis--new sites of synthesis, or much ado about nothing?

The primary adrenocortical steroids are aldosterone, synthesized in the outermost layer of cells of the adrenal cortex, the zona glomerulosa; and cortisol and corticosterone, synthesized in the next layer, or zona fasciculata. Young et al. (1) have presented data in this journal complementing other suggestions that the heart is capable of synthesizing adrenocortical steroids that have physiological or pathophysiological importance through paracrine or autocrine effects (2–6). Aldosterone produced in the zona glomerulosa is released into the circulation, to be carried to various target organs throughout the body, where it binds the mineralocorticoid receptor. This receptor, like others in the steroid receptor superfamily, acts as a transcription factor modulating the transcription of message for several proteins, many of which have not been completely characterized. Aldosterone enhances the vectorial transfer of sodium in transport epithelia (7), increases the blood pressure through its action in the brain via central sympathetic neurons, some of which alter renal function (8, 9), and promotes hypertrophy and fibrosis through direct effects on the heart and vessels (10– 13). Left ventricular mass has been found to correlate with plasma aldosterone in patients with both primary aldosteronism and essential hypertension, as well as in a population-based sample (14–16), suggesting that aldosterone plays an important role in cardiac remodeling. Administration of low doses of the aldosterone receptor antagonist spironololactone in the Randomized Aldactone Evaluation Study trial in patients with congestive heart failure decreased cardiovascular related mortality by 30% and morbidity by 35% (17). This low dose of spironolactone did not affect blood pressure, suggesting a direct effect within the heart. In addition to suffering from the effects of excessive circulating aldosterone, the heart has the enzymatic machinery and the synthetic ability to produce aldosterone and other corticosteroids, which might then act in a paracrine and/or autocrine manner (1–6, 18). The synthesis of steroids from cholesterol in tissues other than the adrenal or gonadal glands was first demonstrated by Baulieu and collaborators (19, 20), who demonstrated steroid synthesis within the central nervous system. They called the products of this de novo synthesis “neurosteroids” (19, 20). Subsequent studies by Takeda and colleagues (21– 25) have demonstrated that human vascular endothelial and smooth muscle cells in vitro and rat mesenteric artery ex vivo release aldosterone and corticosterone into the culture and perfusion media and that cardiovascular cells express and regulate the expression of the enzymes in the late pathway in the biosynthesis of corticosteroids including the 11 -hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2). Studies by Delcayre’s group (3) demonstrated that the ex vivo perfused rat heart released corticosterone and aldosterone into the perfusate. As in the adrenal gland, angiotensin II or ACTH increased both the release of these steroids into the perfusate and their concentration in the heart at the end of the perfusion (3). They also demonstrated that aldosterone synthase mRNA expression in the heart was regulated by the infusion of angiotensin II and by chronic sodium depletion. Aldosterone synthase activity was demonstrated by incubating tritiated deoxycorticosterone with heart homogenates and measure of aldosterone generation (3). Experimental myocardial infarction resulted in a 2-fold increase in aldosterone synthase mRNA and a 3.7-fold increase in aldosterone content in adjacent noninfarcted myocardium (26). The increase was blocked by the administration of an angiotensin II receptor blocker (26). These studies suggested that aldosterone biosynthesis participates in cardiac remodeling after myocardial infaction. Cardiac aldosterone production, aldosterone synthase enzymatic activity, and the expression of aldosterone synthase mRNA were also increased in the stroke-prone spontaneously hypertensive rat in comparison to Wistar Kyoto (WKY) control rats. Aldosterone production and aldosterone synthase mRNA expression were also increased by adrenalectomy (4). In contrast to what occurs in the adrenal gland, chronic sodium loading increased aldosterone synthase mRNA, aldosterone synthase activity, and aldosterone release from perfused WKY rat hearts (5). Expression of the aldosterone synthase gene differs depending on the strain of rat. The heart of the Sprague Dawley rat expresses the aldosterone synthase gene after chronic stimulation with angiotensin II, but not under basal conditions as is reported for the WKY or Spontaneously Hypertensive Rat (18). Two different strains of mouse heart do not express the aldosterone synthase (1), indicating that the expression of steroidogenic enzymes varies according to the species and strains studied. The mRNA for the P-450scc, 3 -ol-dehydrogenase, 21hydroxylase, and 11 -hydroxylase were detected in the human heart using RT-PCR and Southern blotting at levels 100to 10,000-fold lower than those in the adrenal. The aldosterone synthase mRNA was only detected in fetal human heart and aortic samples. Young et al. (1) did not find 11 hydroxylase and aldosterone synthase mRNA expression in normal human heart samples, but did find it in samples of hearts in congestive heart failure. This suggests that under the chronic stress of congestive heart failure, the heart is stimulated to synthesize aldosterone with possible deleterious paracrine or autocrine effects (1). Simultaneously, plasma levels of aldosterone in the anterior interventricular vein, coronary sinus, and aortic root of control people and patients with left ventricular systolic dysfunction or left ventricular diastolic dysfunction were collected by Mizuno et al. (6). Plasma levels of aldosterone in these patients were not different from control subjects. However, aldosterone levels were significantly higher in the anterior interventricular vein 0013-7227/01/$03.00/0 The Journal of Clinical Endocrinology & Metabolism 86(11):5118–5120 Printed in U.S.A. Copyright © 2001 by The Endocrine Society