Angiotensin II Overstimulation Leads to an Increased Susceptibility to Dilated Cardiomyopathy and Higher Mortality in Female Mice.

Heart failure (HF) is associated with high mortality and affects men and women differently. The underlying mechanisms for these sex-related differences remain largely unexplored. Accordingly, using mice with cardiac-specific overexpression of the angiotensin II (ANGII) type 1 receptor (AT1R), we explored male-female differences in the manifestations of hypertrophy and HF.

Reduction in Na(+) current by angiotensin II is mediated by PKCα in mouse and human-induced pluripotent stem cell-derived cardiomyocytes.

Background: Ventricular arrhythmias and sudden cardiac deaths are among the leading causes of mortality in patients with heart failure, and the underlying mechanisms remain incompletely understood. Chronic elevation of angiotensin II (ANGII) is known to be one of the main contributors to heart failure.

Objective: We tested whether ANGII can alter ventricular conduction and Na(+) current using transgenic mice with cardiomyocyte-restricted overexpression of ANGII type 1 receptor (AT1R).

Overexpression of type 1 angiotensin II receptors impairs excitation-contraction coupling in the mouse heart.

Transgenic mice that overexpress human type 1 angiotensin II receptor (AT(1)R) in the heart develop cardiac hypertrophy. Previously, we have shown that in 6-mo AT(1)R mice, which exhibit significant cardiac remodeling, fractional shortening is decreased. However, it is not clear whether altered contractility is attributable to AT(1)R overexpression or is secondary to cardiac hypertrophy/remodeling.

Electrical remodeling in a transgenic mouse model of alpha1B-adrenergic receptor overexpression.

Cardiac-specific overexpression of wild-type alpha(1B)-adrenergic receptors (alpha(1B)-AR) in mice predisposes to dilated cardiomyopathy and sudden death. Although alpha-adrenergic stimulation is thought to contribute to induction of arrhythmias in heart failure, the electrophysiological consequences of chronic alpha(1)-adrenergic activation have not been clearly defined. Thus we characterized ventricular repolarization and monitored incidence of spontaneous arrhythmias in end-stage heart failure alpha(1B)-AR mice (9-12 mo) and younger alpha(1B)-AR mice (2-3 mo) that do not present signs of heart failure.

Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization.

Aims: Mice with cardiac-specific overexpression of human angiotensin II type 1 receptor (AT1R) undergo cardiac remodelling and die prematurely of sudden death. Since excessive QT prolongation is a major risk factor for ventricular arrhythmias and sudden death, we hypothesize that chronic stimulation of AT1R might contribute to sudden death by promoting delayed repolarization and ventricular arrhythmias.

Methods: In the present study, a detailed analysis of ventricular repolarization parameters was undertaken in AT1R mice.

Sex and strain differences in adult mouse cardiac repolarization: importance of androgens.

Objective: Gender differences in mouse cardiac repolarization have been reported to be due to the stimulatory action of androgens on the ultrarapid delayed rectifier K(+) current (I(Kur)) and its underlying Kv1.5 channel. To confirm the regulation of ventricular repolarization by androgens, the present study compared two strains of mice (CD-1 and C57BL/6) that present different androgen levels.