Angiotensin II infusion (200 ng/kg per minute) in mice with cardiomyocyte-specific mineralocorticoid receptor overexpression induced additive effects on left ventricular hypertrophy and fibrosis.
Does Angiotensin II infusion induce cardiac remodeling and dysfunction in mice with cardiomyocyte-specific human mineralocorticoid receptor overexpression?
The additive deleterious effects of Ang II and MR activation on cardiac remodeling and diastolic dysfunction suggest a potential mechanistic rationale for combined Ang II and MR antagonism in heart failure with preserved ejection fraction.
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.
Zhang et al. (Mon,) conducted a other in Cardiac remodeling. Angiotensin II vs. Vehicle and control littermates was evaluated on Cardiac consequences including left ventricle mass/body weight, hypertrophy, and diastolic dysfunction. Angiotensin II infusion (200 ng/kg per minute) in mice with cardiomyocyte-specific mineralocorticoid receptor overexpression induced additive effects on left ventricular hypertrophy and fibrosis.