Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice.
Experimental and clinical evidence suggests kinin involvement in adaptive myocardial growth. Kinins are growth-inhibitory to cardiomyocytes. Knockout of kinin B2 receptor (B2R) signaling causes dilated and failing cardiomyopathy in 129/J mice, and a 9-bp deletion polymorphism of human B2R is associated with reduced receptor expression and exaggerated left ventricular growth response to physical stress. We reasoned that genetic background and aging may significantly influence the impact of B2R mutation on cardiac phenotype. The theory was challenged in C57BL/6 mice, a strain that naturally differs from the 129/J strain, carrying 1 instead of 2 renin genes. C57BL/6 B2R knockouts (B2R-KO) showed higher blood pressure and heart rate levels (P<0.05) compared with wild-type controls (WT) at all ages examined. At 12 months, left ventricular contractility and diastolic function were mildly altered (P<0.05) and histological and morphological analyses revealed ventricular hypertrophy and cardiomyocyte enlargement in B2R-KO (P<0.01). Reparative fibrosis was enhanced by 208% and capillary density reduced by 38% (P<0.01). Functional and structural alterations induced by B2R deletion in C57BL/6 mice were less severe than those reported previously in the 129/J strain. We conclude that interaction of B2R signaling with other genetic determinants influences aging-related changes in myocardial structure and function. These findings may help us understand the role of kinins in the development of cardiac failure.
Maestri
Roberta
R
Experimental Medicine and Gene Therapy Unit, Istituto Nazionale Biotecnologie e Biosistemi, Osilo, Italy.
Milia
Anna Franca
AF
Salis
Maria Bonaria
MB
Graiani
Gallia
G
Lagrasta
Costanza
C
Monica
Manuela
M
Corradi
Domenico
D
Emanueli
Costanza
C
Madeddu
Paolo
P
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001808:Blood Vessels / Q000473:pathology* / Q000503:physiopathology; D001835:Body Weight / Q000502:physiology; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015999:Multivariate Analysis; D009929:Organ Size; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000235:genetics / Q000502:physiology*
D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin