Avoiding vicious circles: mineralocorticoid receptor antagonism prevents vascular oxidative stress early after myocardial infarction.

Oxidative stress is thought to play a key role in the initiation and progression of cardiovascular diseases. Increased formation of reactive oxygen species (ROS) leads to endothelial dysfunction through the breakdown of NO, promotes proinflammatory gene expression, and increases the sympathetic tone. A multitude of stimuli including inflammation, cardiovascular risk factors like hypertension and cigarette smoke as well as a broad spectrum of hormones increase the systemic oxidative stress. Among these elements, however, angiotensin II is probably the most robust stimulus for ROS, which derive from Nox1and Nox2-containing NADPH oxidases. In fact, angiotensin II activates and induces these ROS-generating enzymes. Angiotensin II is also the classic stimulus for the release of aldosterone. Interestingly, also aldosterone is an independent stimulus for vascular ROS production. This steroid hormone induces components of the NADPH oxidase like p47phox1 and p22phox and acutely increases ROS production in vascular cells2 probably through EGF receptor transactivation. Importantly, ROS may be mandatory for the deleterious effects of aldosterone in the cardiovascular system: for example, genetic deletion of the Nox2-containing NADPH oxidases prevents the aldosterone-induced interstitial fibrosis in the mouse heart.3 Furthermore, antioxidants prevent the aldosterone-induced expression of intercellular adhesion molecule-1 and MCP-1 as well as tumor necrosis factor in the rat heart.4 On such a basis it is possible that blockade of the mineralocorticoid receptor by either spironolactone or the more specific aldosterone antagonist eplerenone is beneficial for vascular function in situations of increased aldosterone formation such as chronic congestive heart failure5 or experimental application of angiotensin II.6 In this issue of Hypertension, Sartorio et al7 extend this concept and demonstrate that blockade of mineralocorticoid receptors at the time of myocardial infarcts to a large extent prevents the vascular dysfunction occurring in the early postinfarction period. Eplerenone attenuated the development of aortic endothelial dysfunction, and it prevented the loss of the stimulatory phosphorylation of endothelial NO synthase (eNOS) on serine 1177. Furthermore, this aldosterone antagonist blocked the vascular induction of the angiotensin converting enzyme (ACE) as well as of the p22phox component of the NADPH oxidase. Finally, eplerenone also prevented the infarction-induced downregulation of manganese superoxide dismutase (MnSOD). All these effects resulted in a blockade of the development of infarction-induced vascular oxidative stress. These observations are remarkable and important for several reasons. From the clinical point of view, they may help to understand why an early initiation of therapy with eplerenone in the EPHESUS trial resulted in less mortality than a late initiation. The pathophysiological situation shortly after a large myocardial infarction is also considerably different and more dynamic than the chronic heart failure situation. In the latter, neurohumoral activation dominates, which is just initiated in the early postinfarct time. Moreover, the resolution of the fresh myocardial infarction results in considerable systemic inflammation, a process that elicits oxidative stress per se and probably contributes to vascular dysfunction. It is intriguing that even in such a complex scenario the selective interference with the aldosterone system is sufficient to prevent vascular dysfunction. Two aspects may aid to understand this phenomenon. The down-stream effectors of aldosterone overlap with those of inflammatory cytokines and angiotensin II, and sub-threshold concentrations of the individual hormone may lead to biological effects due to cross talk. Aldosterone, for example, potentiates the activation of ERK1/2 and JNK by angiotensin II.2 The neurohumoral activation that develops early after myocardial infarction is a consequence of several selfenergizing loops, which involve aldosterone as a critical element. Aldosterone maintains AT1 receptor level8 and increases the expression of ACE5 as well as that of subunits of the NADPH oxidase,1 which will further increase and sustain neurohumoral activation. Even the oxidative stress induced by aldosterone is able to enter a vicious circle. The initial ROS, released in response to aldosterone and angiotensin II, promote an uncoupling of eNOS,1 as well as ROS-mediated activation of NADPH oxidase9 and even ROS-dependent induction of components of the NADPH oxidase10 (Figure). That such complex systems are indeed operative in vivo is impressively demonstrated by the observation of Sartorio et al that eplerenone prevents the vascular induction of p22phox as well as of ACE after myocardial infarction.7 Further evidence for such a self-energizing system comes from the observations that inhibition of the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. Correspondence to Ralf P. Brandes, Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail [email protected] (Hypertension. 2007;50:842-843.) © 2007 American Heart Association, Inc.