How does the endocrine system work with the cardiovascular system

This special issue on cardiovascular hormones is a celebration of the contribution that John Funder has made to science and to mentoring, to his involvement in numerous scientific societies, government and non-government organizations, and to his joi de vie. Anyone who has had the pleasure of meeting Funder cannot help but be impressed by his intelligence, his broad classical knowledge, his wit and humour and his larger-than-life presence. He was one of the first people to recognize the importance of and develop the field of cardiovascular endocrinology [

]. The papers in this issue vividly demonstrate the convergence of research in endocrinology, lipid and glucose metabolism and cardiovascular function and disease. They also illustrate the breadth and depth of Funder's interest and influence ranging from fundamental work on receptor recognition through to clinical medicine. The first group of four papers in this issue deals with the super family of nuclear receptors (NR), particularly aldosterone.

Aldosterone, discovered 50 years ago, has been a relatively neglected hormone. The major mineralocorticoid in mammals, its function and mode of action on Na+ transporters and water and electrolyte balance were quickly established. The major factors controlling aldosterone synthesis and release from the zona glomerulosa adrenal gland (ACTH, angiotensin and potassium) were also immediately determined. Some clinical syndromes describing lack (adrenal crisis) and overproduction of aldosterone were immediately identified. Primary aldosteronism (PAL), a condition described by Conn in 1954 as hypertension associated with hypokalaemia, hypernatraemia, hypochloraemia and metabolic acidosis owing to autonomous adrenal production either from adrenal hyperplasia or from a cortical adenoma, was the first condition to link the electrolyte, blood pressure and cardiovascular actions of aldosterone. Much later the syndrome of apparent mineralocorticoid excess (AME) was described and more recently the molecular mechanism of this disease from mutations in the 11-β-hydroxysteroid dehydrogenase (11-βHDS2) Type II gene has been unravelled by Funder and others [

,

].

However, the cloning, localization and characterization of the glucocorticoid (GR) and mineralocorticoid (MR) steroid receptors uncovered a paradox. These were all relatively nonspecific receptors – glucocorticoids bound equally well to the MR as did aldosterone. Yet the plasma levels of cortisol were significantly higher than aldosterone. What then conferred the specificity for the cellular action of steroids? Funder's concept that it was because of a ‘guardian angel’, an enzyme, β-hydroxysteroid dehydrogenase (11-βHSD2) expressed in the hormone target tissues that metabolized cortisol into corticosterone (which does not bind to the MR, thus providing the specificity) was a seminal discovery [

]. The papers of Pearce and Fuller in this issue describe other factors that confer specificity to the MR and the important post-receptor and genomic effects of aldosterone that are vital for understanding how steroids act.

The papers that follow by the Baxter and Evans groups describe the possible cardiovascular implications of other members of the ‘NR super family’ [

]. Baxter also deals with receptor recognition and selectivity, this time with the thyroid receptor (TR). Thyroid hormones act on two distinct receptors, TRα and TRβ, and this paper explores the idea that it might be possible to separate the metabolic from the cardiovascular effects of thyroid activity, thus producing favourable effects on metabolism and lipids without the undesirable cardiovascular action of tachycardia. He also presents preliminary data on a non-iodine thyromimetic analogue GC-1 that shows some TR selectivity in that it reduces cholesterol and triglycerides, as well as inducing fat loss at doses that do not produce tachycardia. Although this is a promising therapeutic approach for treating the metabolic syndrome, he points out that much more work needs to be carried out before it can be used in humans.

Evans and his group extend the idea of the connection between NR, metabolism, the metabolic syndrome and cardiovascular disease, particularly atherosclerosis. They describe the metabolic and cardiovascular effects of two recently identified members of the NR family, peroxisome proliferator-activated receptors (PPARs) and liver-X receptors (LXRs). Both these nuclear receptors are activated by sterols including modified cholesterol and other lipids, which act as ligands. Their mode of action involves modulating transcription of target genes, usually by binding to the gene promoter region. As they describe so elegantly, this regulates key cellular processes involved in lipid and glucose metabolism and transport, including the reverse cholesterol pathway and the action of insulin leading to favourable effects on cholesterol levels, insulin sensitivity and obesity. Furthermore PPARs and LXRs are also present in macrophages and influence macrophage behaviour and inflammation in the vascular wall. This linking of metabolic effects and the inflammatory process could be particularly important in atherosclerosis and offers an alternative strategy for treating this common disease and its complications.

In the past few years the classical view of the rennin–angiotensin–aldosterone system (RAAS) has developed a new paradigm. These systems are no longer viewed simply as hormones synthesized and secreted by highly specialized glands that then circulate in the blood and bind to receptors in distant target organs where they exert their physiological effects. It is now increasingly recognized that many components of the RAAS can be synthesized in other tissues where they possibly have autocrine or paracrine effects [

,

]. Aldosterone and the MR have now been reported to be produced in many tissues that are involved in cardiovascular homeostasis (heart, blood vessels and kidney) [

] as well as the brain. Also their actions in these tissues have been shown to be through MR or by non-genomic non-receptor-mediated pathways [

]. In many cases they are activated only following tissue injury and repair. Again Funder's group have contributed significantly in this area [

]. Aldosterone, like angiotensin, has been shown to produce oxidative stress and be a pro-inflammatory, pro-fibronic and pro-thrombotic agent. It has been implicated in pathophysiology of hypertension, vasculopathy, left ventricular hypertrophy and fibrosis, endothelial dysfunction and heart failure [

,

]. In this issue Burrell et al. deal with a further development in the RAAS, the identification of a human angiotensin converting enzyme (ACE) homologue, ACE2. This enzyme, which differs from ACE, is responsible for the production of angiotensin (1–7) from angiotensin II (1–8). Angiotensin (1–7) has actions that generally oppose angiotensin II and might act as a counter regulatory system. Natriuretic peptides (NPs) produced by the heart, and therefore truly cardiovascular hormones, can be seen as biological antagonists of the RAAS causing vasodilation, natriuresis and diuresis. They are also antiproliferative and antifibrogenic. Richards et al. illustrate the increasing clinical utility and possible therapeutic benefits of the natriuretic peptides in heart failure.

In a timely and comprehensive review, Thomas outlines what is known about the newest of the possible cardiovascular hormones – urotensin. Urotensin, although newly rediscovered, is one of the oldest hormones, first described in fish and lower organisms. The demonstration that it is the most potent vasoconstrictor discovered in primates, and possibly in man, to date has led to increased interest in its role in cardiovascular function and disease.

Finally, Gluckman proposes that many metabolic phenotypes and many of the precedents for cardiovascular and metabolic diseases might be influenced not only by genes but also by the fetal environment and by predictive adaptive response (PARs). This programming during early life could give rise to insulin resistance, the metabolic syndrome and even diabetes. These are all very interesting concepts, many of which await confirmation but it is now apparent that modern molecular techniques and knowledge of gene–environment interactions have given us the methodological platforms and ability to vigorously test these ideas.

The RAAS has had a rich and rewarding past and the development of drugs to block the system has led to major advances in cardiovascular therapeutics. It can be confidently predicted that further advances in understanding the cardiovascular effect (both receptor and non-receptor-mediated) and both genomic and non-genomic effects of peptide and nuclear receptors will occur in the next 50 years. No doubt Funder's group will make a significant contribution to these areas. Advances in this field hold the possibility of leading to new therapies not only for cardiovascular disease but also for the metabolic syndrome, diabetes and obesity, still scourges of the world.

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