Original Article
Genetic Enhancement of Ventricular Contractility Protects against Pressure-Overload-Induced Cardiac Dysfunction

https://doi.org/10.1016/j.yjmcc.2004.07.010Get rights and content

Abstract

In response to pressure-overload, cardiac function deteriorates and may even progress to fulminant heart failure and death. Here we questioned if genetic enhancement of left ventricular (LV) contractility protects against pressure-overload. Transgenic (TG) mice with cardiac-restricted overexpression (66-fold) of the α1A-adrenergic receptor (α1A-AR) and their non-TG (NTG) littermates, were subjected to transverse aorta constriction (TAC)-induced pressure-overload for 12 weeks. TAC-induced hypertrophy was similar in the NTG and TG mice but the TG mice were less likely to die of heart failure compared to the non-TG animals (P <0.05). The hypercontractile phenotype of the TG mice was maintained over the 12-week period following TAC with LV fractional shortening being significantly greater than in the NTG mice (42±2 vs 29±1%, P <0.01). In the TG animals, 11-week β-AR-blockade with atenolol neither induced hypertrophy nor suppressed the hypercontractile phenotype. The hypertrophic response to pressure-overload was not altered by cardiac α1A-AR overexpression. Moreover, the inotropic phenotype of α1A-AR overexpression was well maintained under conditions of pressure overload. Although the functional decline in contractility with pressure overload was similar in the TG and NTG animals, given that contractility was higher before TAC in the TG mice, their LV function was better preserved and heart failure deaths were fewer after induction of pressure overload.

Introduction

The β1-adrenergic receptor (AR) is the predominant AR-subtype mediating inotropic and chronotropic responses to sympathoadrenergic stimulation of the heart. Although the α1-ARs also mediate a positive inotropic response [1], [2], [3] in the healthy heart this effect is weak compared to that of the β1-AR.

Recently, we showed that transgenic (TG) mice with up to a 170-fold increase in cardiac α1A-ARs did not develop myocardial hypertrophy and showed markedly enhanced inotropy but not lusitropy [4]. The lack of hypertrophy in this TG model was surprising, given that evidence from numerous studies has implicated α1A-AR-activation in the pathogenesis of hypertrophy [5], [6], [7], [8], [9], [10]. Nevertheless, this conclusion was largely based on studies of isolated cardiomyocytes of the rat, a species that may be atypical, since, in contrast to those of virtually all other mammals, including humans and the mouse, they show a 5~10-fold higher level of cardiac α1-AR density [11]. Consistent with this interpretation, differences in α1-AR signalling pathways in cultured rat versus mouse cardiomyocytes have been demonstrated [12], [13]. On the other hand, given that the TG mice display increased expression of atrial natriuretic factor (ANF) [4], it is also possible that even though hypertrophy is not overtly manifested in these mice, their hypertrophic signalling is nonetheless sensitized. If this is the case, these mice should develop more marked hypertrophy in response to pathological stimuli, such as pressure-overload. Alternatively, resistance of the α1A-AR TG model to hypertrophy-development may be due to the restraining influences of an inhibitory pathway. For example, using cultured rat cardiomyocytes, Schafer et al. [14] described cross-talk between β1- and α1-ARs in which concomitant activation of the former suppresses α1-AR-mediated hypertrophic signalling. This raises the question: does this inhibitory cross-talk account for the absence of hypertrophy in the α1A-AR TG mice? More importantly, given that increased cardiac work, such as that associated with pressure-overload, leads to a functional deterioration that can progress to heart failure, the α1A-AR TG mice provide a convenient model to test if enhanced inotropic drive preserves ventricular function in disease states or with chronic β-blockade.

Here, we show that development of pressure-overload hypertrophy is neither enhanced nor impaired in the α1A-AR TG animals, and that contrary to the extant in vitro data in the rat [14] the present in vivo study in the mouse provides no evidence for cross-talk between β1-ARs and α1A-AR-coupled signalling pathways. Importantly, enhanced inotropy by the α1A-AR preserves cardiac function in the face of pressure-overload, with a consequent reduction in heart failure development and related death.

Section snippets

Animals, surgery and drug treatment

A1A2 TG line with 66-fold overexpression of the rat α1A-AR, on a FVB/N genetic background, was used at three to four months of age [4]. All experimental procedures were approved by animal ethics committees. Animals were genotyped, anesthetized with a mixture of ketamine/xylazine/atropine (100/20/1.2 mg/kg, respectively, i.p.), as described previously [4], [15], [16], and then subjected to either a 60% transverse aorta constriction (TAC) or a sham-operation. Cardiac function was evaluated at 7

Phenotype assessment

Absence of hypertrophy in the TG mice was evident from the lack of change in echocardiographic LV mass or in LV weight compared with the NTG littermates (Table 1). Micromanometry showed similar arterial pressures and heart rates in both groups. The hypercontractile phenotype, previously documented in the A1A1 α1A-AR TG line with 170-fold transgene expression [4], was also apparent in the A1A2 line. Thus, the TG mice had significantly smaller LVDs, higher FS and WTI, a steeper slope of aortic

Discussion

In the present study, we have made the following major observations. First, the enhanced inotropy of α1A-AR TG mice is well maintained during pressure-overload, and contributes to better LV contractile function. Second, failure of α1A-AR TG mice to develop hypertrophy is not due to a global defect in their hypertrophic machinery, since they maintain a normal ability to develop pressure-overload hypertrophy comparable to that in NTG mice. Third, β1-AR inhibition of α1A-AR-mediated hypertrophy,

Acknowledgments

Supported in part by grants from the National Heart Foundation, Australia and National Health and Medical Research Council, Australia. We are grateful to Dr. Susan Steinberg for advice on the evaluation of α1A-AR signalling pathways and Dr. Jörg Heierhorst and Bryony Mearns for assistance with some of the signalling studies.

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