Dilated and failing cardiomyopathy in bradykinin B2 receptor knockout mice

Abstract

Background - The activation of B2 receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure. Methods and Results - To test whether the absence of bradykinin B2 receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B2 receptor gene knockout (B2(-/-)), heterozygous (B2(+/-)), and wild-type (B2(+/+)) mice. The BP of B2(-/-) mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B2(+/+), P<0.01). In B2(+/-) mice, BP elevation was delayed. At 40 days, the heart rate was higher (P<0.01) in B2(-/-) and B2(+/-) than in B2(+/+) mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B2(-/-) and B2(+/-) mice was accelerated, leading at 360 days to a LV weight-to-body weight ratio that was 9% and 17% higher, respectively, than that of B2(+/+) mice. In B2(-/-) mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B2(+/+) mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B2(+/+) mice, p<0.01), and reparative fibrosis. Conclusions - The disruption of the bradykinin B2 receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.