Coronary endothelial dysfunction after cardiomyocyte-specific mineralocorticoid receptor overexpression

• Published in: American journal of physiology. Heart and circulatory physiology 2011-06, Vol.300 (6), p.H2035-H2043
• Main Authors: Favre, Julie, Gao, Ji, Zhang, An Di, Remy-Jouet, Isabelle, Ouvrard-Pascaud, Antoine, Dautreaux, Brigitte, Escoubet, Brigitte, Thuillez, Christian, Jaisser, Frédéric, Richard, Vincent
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Animals; Ascorbic Acid - pharmacology; Cardiomyocytes; Cardiovascular disease; Cell Communication - physiology; Coronary Vessels - cytology; Coronary Vessels - physiopathology; Endothelium, Vascular - cytology; Endothelium, Vascular - physiopathology; Hormones; Humans; Mice; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Models, Animal; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Nitric oxide; Nitric Oxide - metabolism; Phosphorylation; Reactive Oxygen Species - metabolism; Receptors, Mineralocorticoid - drug effects; Receptors, Mineralocorticoid - metabolism; Vitamin E - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00552.2010

The deleterious effects of aldosterone excess demonstrated in cardiovascular diseases might be linked in part to coronary vascular dysfunction. However, whether such vascular dysfunction is a cause or a consequence of the changes occurring in the cardiomyocytes is unclear. Moreover, the possible link between mineralocorticoid receptor (MR)-mediated effects on the cardiomyocyte and the coronary arteries is unknown. Thus we used a mouse model with conditional, cardiomyocyte-specific overexpression of human MR (hMR) and observed the effects on endothelial function in isolated coronary segments. hMR overexpression decreased the nitric oxide (NO)-mediated relaxing responses to acetylcholine in coronary arteries (but not in peripheral arteries), and this was prevented by a 1-mo treatment either with an MR antagonist, vitamin E/vitamin C, or a NADPH oxidase inhibitor. hMR overexpression did not affect coronary endothelial NO synthase content nor its level of phosphorylation on serine 1177, but increased cardiac levels of reactive oxygen species, cardiac NADPH oxidase (NOX) activity, and expression of the NOX subunit gp91phox, which was limited to endothelial cells. Thus an increase in hMR activation, restricted to cardiomyocytes, is sufficient to induce a severe coronary endothelial dysfunction. We suggest a new paracrine mechanism by which cardiomyocytes trigger a NOX-dependent, reactive oxygen species-mediated coronary endothelial dysfunction.