Cardiac Hypertrophy and Microvascular Deficit in Kinin B2 Receptor Knockout Mice

Abstract

Abstract-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 (PϽ0.05) compared with wild-type controls (WT) at all ages examined. At 12 months, left ventricular contractility and diastolic function were mildly altered (PϽ0.05) and histological and morphological analyses revealed ventricular hypertrophy and cardiomyocyte enlargement in B2R-KO (PϽ0.01). Reparative fibrosis was enhanced by 208% and capillary density reduced by 38% (PϽ0.01).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.

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Mild degenerative and fibrotic changes are observed in the myocardium of aging B 2 receptor knockout mice (Maestri et al, 2003). All these findings support a protective role of the endogenous kallikrein-kinin system on various aspects of cardiovascular and renal function.…”

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…Thus, besides reducing angiotensin II production, ACE inhibitors may contribute to the control of blood pressure by increasing the concentration of bradykinin. Mice that are genetically null for the B2 receptor have an increase in blood pressure on some genetic backgrounds, but this increase is much less or absent on a C57BL/6 genetic background (Trabold et al, 2002;Maestri et al, 2003).…”

Kallikrein–Kinin System in Neovascularization

“…Interestingly, no vascular abnormalities have been observed in all known knockout models for the KKS, such as the B1, B1/B2 double, kininogen I, and tissue kallikrein knockout mice. The only exception is the observation of a mild capillary rarefaction in the heart of B2 knockout mice, 21 which was not described in another study. 22 This indicates that the KKS is not essential for the embryonic development of the vascular system but centrally involved in its adaptation to ischemic stress.…”