Ensayos

European Journal of Endocrinology (2007) 157 545–559

ISSN 0804-4643

INVITED REVIEW

Glucocorticoids and Cardiovascular Disease
Brian R Walker
Endocrinology Unit, Queen’s Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK (Correspondence should be addressed to B R Walker; Email:b.walker@ed.ac.uk) This article is based on the presentation for the European Journal of Endocrinology Prize Lecture 2004 at the European Society of Endocrinology Meeting at Budapest, Hungary

Abstract
Chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic–pituitary– adrenalaxis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11b-hydroxysteroid dehydrogenase enzymes.These effects influence vascular function, atherogenesis and vascular remodelling following intravascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury. Theconclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease. European Journal of Endocrinology 157 545–559

Introduction
Atherosclerosis and its occlusive vascular consequences remain the most common cause of death in many parts of the world. Several risk factors for the development ofatheroma are amenable to treatment, including hypercholesterolaemia, hypertension, hyperglycaemia and cigarette smoking. Secular trends show that cardiovascular disease is declining in prevalence in the developed world, and that the outcome from events such as myocardial infarction is improving, in part due to modern cardiological interventions (1). However, there is concern that the pandemic ofobesity and associated metabolic syndrome threatens to reverse these secular trends. In order to make further improvements in the prevalence and outcome of occlusive vascular disease and avoid the threat posed by obesity, we will need to understand more about the complex mechanisms that promote atheromatous plaque formation and instability and determine recovery following occlusive vascular events.This review is focused on the role of glucocorticoids in atherogenesis, and highlights emerging data which suggest that manipulation of glucocorticoid action has important potential in improving the outcome of occlusive vascular disease.
q 2007 Society of the European Journal of Endocrinology

Glucocorticoid signalling and the cardiometabolic responses to stress
Glucocorticoids such as cortisolplay a key role in the response to stress, including following sepsis, trauma, starvation and tissue ischaemia (2). Psychological stress can also activate the hypothalamic–pituitary–adrenal (HPA) axis, although in humans only selected psychological stimuli produce a robust increase in cortisol release. Cortisol induces a host of adaptive responses that may be homeostatic (adjusting systems tofunction normally in the face of a stressful environment) or allostatic (adjusting systems to function in a manner more appropriate to the stressful environment). Glucocorticoids provide a crucial ‘brake’ on innate inflammatory mechanisms, promoting resolution of inflammation (2). Many of these effects of glucocorticoids are relevant to cardiovascular and metabolic regulation, for example to maintain...