Pressure overload causes cardiac hypertrophy in β1-adrenergic and β2-adrenergic receptor double knockout mice

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Abstract
Objective Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not α1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether β-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time. Methods and results Pressure overload was induced by transverse aortic banding in β1-adrenergic and β2-adrenergic receptor double knockout (DβKO) mice, in which the predominant cardiac β-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DβKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and β-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DβKO banded mice, and were significantly greater than in sham controls. Conclusion Despite chronic activation of the cardiac β-adrenergic system being sufficient to induce a pathological hypertrophy, we show that β1-adrenergic and β2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.