Pressure overload causes cardiac hypertrophy in beta1-adrenergic and beta2-adrenergic receptor double knockout mice.
ABSTRACT Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time.
Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO 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 beta-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 DbetaKO banded mice, and were significantly greater than in sham controls.
Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.
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ABSTRACT: The activation state of β-adrenergic receptors (β-ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metabolic rate. In order to achieve homeostasis in vivo, the cellular signals generated by β-AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic knockout models to test directly the role of β1- and/or β2-AR expression on these homeostatic control mechanisms. Despite total absence of β1- and β2-ARs, the predominant cardiovascular β-adrenergic subtypes, basal heart rate, blood pressure, and metabolic rate do not differ from wild type controls. However, stimulation of β-AR function by β-AR agonists or exercise reveals significant impairments in chronotropic range, vascular reactivity, and metabolic rate. Surprisingly, the blunted chronotropic and metabolic response to exercise seen in β1/β2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single β1- and β2-AR knockouts as well as the β1-/β2-AR double knock-out suggest that in the mouse, β-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the β1-AR, whereas vascular relaxation and metabolic rate are controlled by all three β-ARs (β1-, β2-, and β3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular β3-AR responsiveness are also observed in β1-/β2-AR double knockouts. In addition to its ability to define β-AR subtype-specific functions, this genetic approach is also useful in identifying adaptive alterations that serve to maintain critical physiological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed.Journal of Biological Chemistry 06/1999; 274(24):16701-16708. · 4.65 Impact Factor
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ABSTRACT: The aim was to provide meaningful information on the function of the sympathetic system soon after an increased pressure overload on the heart. Noradrenaline storage, turnover, uptake, and synthesis were investigated at 3, 14, and 28 d after aortic banding in rats. Sham operated rats without aortic banding were used as control group. Left ventricle, spleen, and kidney from male Sprague-Dawley rats (175-200 g) were used in this study. Cardiac noradrenaline concentration was decreased at 3 d and 28 d after banding and increased at 14 d; left ventricular mass was increased from 14 d onwards. The rate of change in the specific activity of myocardial noradrenaline (noradrenaline turnover) as well as dopamine beta hydroxylase, an enzyme for noradrenaline synthesis, was unaltered at 3 d, increased at 14 d, and decreased at 28 d after aortic banding. Myocardial [3H]noradrenaline uptake, on the other hand, was decreased at all time points studied. The changes observed in the myocardium at day 14 were specific since noradrenaline turnover rate was unaltered in other peripheral organs such as spleen and kidney. Furthermore, after ganglionic blockade with pentolinium, both sham operated control and banded animals had identical, low noradrenaline turnover rate constants, and significant restoration of cardiac weight and noradrenaline stores was observed in the hearts from banded animals. Noradrenaline turnover and metabolism are altered soon after imposing increased workload on heart. Whether or not the changes in the sympathetic activity are a prerequisites for hypertrophy still remains to be seen.Cardiovascular Research 08/1991; 25(7):579-85. · 5.94 Impact Factor
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ABSTRACT: To study the mechanisms that activate expression of the atrial natriuretic factor (ANF) gene during pressure-induced hypertrophy, we have developed and characterized an in vivo murine model of myocardial cell hypertrophy. We employed microsurgical techniques to produce a stable 35- to 45-mmHg pressure gradient across the thoracic aorta of the mouse that is associated with rapid and transient expression of an immediate-early gene program (c-fos/c-jun/junB/Egr-1/nur-77), an increase in heart weight/body weight ratio, and up-regulation of the endogenous ANF gene. These responses that are identical to those in cultured cell and other in vivo models of hypertrophy. To determine whether tissue-specific and inducible expression of the ANF gene can be segregated, we used a transgenic mouse line in which 500 base pairs of the human ANF promoter region directs atrial-specific expression of the simian virus 40 large tumor antigen (T antigen), with no detectable expression in the ventricles. Thoracic aortic banding of these mice led to a 20-fold increase in the endogenous ANF mRNA in the ventricle but no detectable expression of the T-antigen marker gene. This result provides evidence that atrial-specific and inducible expression of the ANF gene can be segregated, suggesting that a distinct set of regulatory cis sequences may mediate the up-regulation of the ANF gene during in vivo pressure overload hypertrophy. This murine model demonstrates the utility of microsurgical techniques to study in vivo cardiac physiology in transgenic mice and should allow the application of genetic approaches to identify the mechanisms that activate ventricular expression of the ANF gene during in vivo hypertrophy.Proceedings of the National Academy of Sciences 10/1991; 88(18):8277-81. · 9.74 Impact Factor