Hormones and the cardiovascularsystemColin Johnston

Baker Heart Research Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia

This special issue on cardiovascularhormones is a celebration of thecontribution that John Funder hasmade to science and to mentoring, tohis involvement in numerous scien-tific societies, government and non-government organizations, and tohis joi de vie. Anyone who has hadthe pleasure of meeting Fundercannot help but be impressed by

his intelligence, his broad classical knowledge, his wit andhumour and his larger-than-life presence. He was one ofthe first people to recognize the importance of and developthe field of cardiovascular endocrinology [1]. The papers inthis issue vividly demonstrate the convergence of researchin endocrinology, lipid and glucose metabolism andcardiovascular function and disease. They also illustratethe breadth and depth of Funder’s interest and influenceranging from fundamental work on receptor recognitionthrough to clinical medicine. The first group of four papersin this issue deals with the super family of nuclearreceptors (NR), particularly aldosterone.

Aldosterone, discovered 50 years ago, has been a rela-tively neglected hormone. The major mineralocorticoid inmammals, its function and mode of action on Naþ trans-porters and water and electrolyte balance were quicklyestablished. The major factors controlling aldosteronesynthesis and release from the zona glomerulosa adrenalgland (ACTH, angiotensin and potassium) were also imme-diately determined. Some clinical syndromes describing lack(adrenal crisis) and overproduction of aldosterone wereimmediately identified. Primary aldosteronism (PAL), acondition described by Conn in 1954 as hypertension asso-ciated with hypokalaemia, hypernatraemia, hypochlo-raemia and metabolic acidosis owing to autonomousadrenal production either from adrenal hyperplasia orfrom a cortical adenoma, was the first condition to link theelectrolyte, blood pressure and cardiovascular actions ofaldosterone. Much later the syndrome of apparent mineralo-corticoid excess (AME) was described and more recentlythe molecular mechanism of this disease from mutationsin the 11-b-hydroxysteroid dehydrogenase (11-bHDS2)Type II gene has been unravelled by Funder and others [2,3].

However, the cloning, localization and characterizationof the glucocorticoid (GR) and mineralocorticoid (MR)steroid receptors uncovered a paradox. These were all

relatively nonspecific receptors – glucocorticoids boundequally well to the MR as did aldosterone. Yet the plasmalevels of cortisol were significantly higher than aldoster-one. What then conferred the specificity for the cellularaction of steroids? Funder’s concept that it was because ofa ‘guardian angel’, an enzyme, b-hydroxysteroid dehydro-genase (11-bHSD2) expressed in the hormone targettissues that metabolized cortisol into corticosterone(which does not bind to the MR, thus providing thespecificity) was a seminal discovery [4]. The papers ofPearce and Fuller in this issue describe other factors thatconfer specificity to the MR and the important post-receptor and genomic effects of aldosterone that are vitalfor understanding how steroids act.

The papers that follow by the Baxter and Evans groupsdescribe the possible cardiovascular implications of othermembers of the ‘NR super family’ [5]. Baxter also dealswith receptor recognition and selectivity, this time withthe thyroid receptor (TR). Thyroid hormones act on twodistinct receptors, TRa and TRb, and this paper exploresthe idea that it might be possible to separate the metabolicfrom the cardiovascular effects of thyroid activity, thusproducing favourable effects on metabolism and lipidswithout the undesirable cardiovascular action of tachy-cardia. He also presents preliminary data on a non-iodinethyromimetic analogue GC-1 that shows some TR selec-tivity in that it reduces cholesterol and triglycerides, aswell as inducing fat loss at doses that do not producetachycardia. Although this is a promising therapeuticapproach for treating the metabolic syndrome, he pointsout that much more work needs to be carried out before itcan be used in humans.

Evans and his group extend the idea of the connectionbetween NR, metabolism, the metabolic syndrome andcardiovascular disease, particularly atherosclerosis. Theydescribe the metabolic and cardiovascular effects of tworecently identified members of the NR family, peroxisomeproliferator-activated receptors (PPARs) and liver-Xreceptors (LXRs). Both these nuclear receptors areactivated by sterols including modified cholesterol andother lipids, which act as ligands. Their mode of actioninvolves modulating transcription of target genes, usuallyby binding to the gene promoter region. As they describe soelegantly, this regulates key cellular processes involved inlipid and glucose metabolism and transport, including thereverse cholesterol pathway and the action of insulinleading to favourable effects on cholesterol levels, insulinsensitivity and obesity. Furthermore PPARs and LXRs areCorresponding author: C. Johnston (colin.johnston@baker.edu.au).

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also present in macrophages and influence macrophagebehaviour and inflammation in the vascular wall. Thislinking of metabolic effects and the inflammatory processcould be particularly important in atherosclerosis andoffers an alternative strategy for treating this commondisease and its complications.

In the past few years the classical view of the rennin–angiotensin–aldosterone system (RAAS) has developed anew paradigm. These systems are no longer viewed simplyas hormones synthesized and secreted by highly special-ized glands that then circulate in the blood and bind toreceptors in distant target organs where they exert theirphysiological effects. It is now increasingly recognized thatmany components of the RAAS can be synthesized in othertissues where they possibly have autocrine or paracrineeffects [6,7]. Aldosterone and the MR have now beenreported to be produced in many tissues that are involvedin cardiovascular homeostasis (heart, blood vessels andkidney) [8] as well as the brain. Also their actions in thesetissues have been shown to be through MR or by non-genomic non-receptor-mediated pathways [9]. In manycases they are activated only following tissue injury andrepair. Again Funder’s group have contributed signifi-cantly in this area [10]. Aldosterone, like angiotensin, hasbeen shown to produce oxidative stress and be a pro-inflammatory, pro-fibronic and pro-thrombotic agent. Ithas been implicated in pathophysiology of hypertension,vasculopathy, left ventricular hypertrophy and fibrosis,endothelial dysfunction and heart failure [11,12]. In thisissue Burrell et al. deal with a further development in theRAAS, the identification of a human angiotensin convert-ing enzyme (ACE) homologue, ACE2. This enzyme, whichdiffers from ACE, is responsible for the production ofangiotensin (1–7) from angiotensin II (1–8). Angiotensin(1–7) has actions that generally oppose angiotensin II andmight act as a counter regulatory system. Natriureticpeptides (NPs) produced by the heart, and therefore trulycardiovascular hormones, can be seen as biological anta-gonists of the RAAS causing vasodilation, natriuresis anddiuresis. They are also antiproliferative and antifibro-genic. Richards et al. illustrate the increasing clinicalutility and possible therapeutic benefits of the natriureticpeptides in heart failure.

In a timely and comprehensive review, Thomasoutlines what is known about the newest of thepossible cardiovascular hormones – urotensin. Uroten-sin, although newly rediscovered, is one of the oldesthormones, first described in fish and lower organisms.The demonstration that it is the most potent vasocon-strictor discovered in primates, and possibly in man, todate has led to increased interest in its role incardiovascular function and disease.

Finally, Gluckman proposes that many metabolic pheno-types and many of the precedents for cardiovascular andmetabolic diseases might be influenced not only by genes butalso by the fetal environment and by predictive adaptiveresponse (PARs). This programming during early life couldgive rise to insulin resistance, the metabolic syndrome andeven diabetes. These are all very interesting concepts,many of which await confirmation but it is nowapparent that modern molecular techniques andknowledge of gene–environment interactions havegiven us the methodological platforms and ability tovigorously test these ideas.

The RAAS has had a rich and rewarding past andthe development of drugs to block the system has led tomajor advances in cardiovascular therapeutics. It canbe confidently predicted that further advances inunderstanding the cardiovascular effect (both receptorand non-receptor-mediated) and both genomic and non-genomic effects of peptide and nuclear receptors willoccur in the next 50 years. No doubt Funder’s groupwill make a significant contribution to these areas.Advances in this field hold the possibility of leading tonew therapies not only for cardiovascular disease butalso for the metabolic syndrome, diabetes and obesity,still scourges of the world.

References

1 Funder, J.W. (2001) Cardiovascular endocrinology: into the newmillennium. Trends Endocrinol. Metab. 12, 283–285

2 Wilson, R.C. et al. (1995) A mutation in the HSD11B2 gene in a familywith apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab.80, 2263–2266

3 White, P.C. et al. (1997) 11b-hydroxysteroid dehydrogenase and thesyndrome of apparent mineralocorticoid excess. Endocr. Rev. 18,135–136

4 Funder, J.W. et al. (1988) Mineralocorticoid action: target-tissuespecificity is enzyme, not receptor, mediated. Science 242, 583–585

5 Xie, W. and Evans, R.M. (2001) Orphan nuclear receptors: the exoticsof xenobiotics. J. Biol. Chem. 276, 37739–37742

6 Dzau, V.J. (1988) Circulating versus local renin-angiotensin system incardiovascular homeostasis. Circulation 77, I4–13

7 Johnston, C.I. (1994) Tissue angiotensin converting enzyme in cardiacand vascular hypertrophy, repair, and remodeling. Hypertension 23,258–268

8 Slight, S.H. et al. (1999) Extra-adrenal mineralocorticoids andcardiovascular tissue. J. Mol. Cell. Cardiol. 31, 1175–1184

9 Losel, R.M. et al. (2002) Nongenomic effects of aldosterone: cellularaspects and clinical implications. Steroids 67, 493–498

10 Young, M. et al. (1994) Mineralocorticoids, hypertension and cardiacfibrosis. J. Clin. Invest. 93, 2578–2583

11 Weber, K.T. et al. (2003) Toward a broader understanding ofaldosterone in congestive heart failure. J. Renin Angiotensin Aldos-terone Syst. 4, 155–163

12 Struthers, A.D. (2001) Aldosterone-induced vasculopathy: a newreversible cause of cardiac death. J. Renin Angiotensin AldosteroneSyst. 2, 211–214

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