title: Cross-talk between mineralocorticoid and angiotensin II signaling for cardiac remodeling.
abstract: Experimental and clinical studies show that aldosterone/mineralocorticoid receptor (MR) activation has deleterious effects in the cardiovascular system that may cross-talk with those of angiotensin II (Ang II). This study, using a transgenic mouse model with conditional and cardiomyocyte-restricted overexpression of the human MR, was designed to assess the cardiac consequences of Ang II treatment and cardiomyocyte MR activation. Two-month-old MHCtTA/tetO-hMR double transgenic males (DTg) with conditional, cardiomyocyte-specific human MR expression, and their control littermates were infused with Ang II (200 ng/kg per minute) or vehicle via osmotic minipump. Ang II induced similar increases in systolic blood pressure in control and DTg mice but a greater increase in left ventricle mass/body weight in DTg than in control mice. In DTg mice, Ang II-induced left ventricle hypertrophy and diastolic dysfunction without affecting systolic function, as assessed by echography. These effects were associated with an increase in the expression of collagens and fibronectin, matrix metalloproteinase 2 and matrix metalloproteinase 9 activities, and histological fibrosis. Ang II treatment of DTg mice did not affect inflammation markers, but oxidative stress was substantially increased, as indicated by gp91 expression, apocynin-inhibitable NADPH oxidase activity, and protein carbonylation. These molecular and functional alterations were prevented by pharmacological MR antagonism. Our findings indicate that the effects of Ang II and MR activation in the heart are additive. This observation may be relevant to the clinical use of MR or of combined Ang II type 1 receptor-MR antagonists for hypertrophic cardiomyopathies or for heart failure, particularly when diastolic dysfunction is associated with preserved systolic function.
authors.affiliation: INSERM U772, College de France, Berthelot, Paris Cedex, France.
authors.forename: An
authors.initials: A
authors.lastname: Di Zhang
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.forename: Christelle
authors.initials: C
authors.lastname: Soukaseum
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Aïcha
authors.initials: A
authors.lastname: Cherfa
authors.forename: Smail
authors.initials: S
authors.lastname: Messaoudi
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004452:Echocardiography; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D020239:Receptor Cross-Talk; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D014662:Vasoconstrictor Agents; D000804:Angiotensin II