P65Adenosine A1-receptor agonism counteracts hypertrophy and fibrosis in response to alpha-adrenergic stimulation

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Abstract

Introduction

Adenosine is an important signaling molecule in the cardiovascular system and has been proposed to exert anti-hypertrophic effects. The precise regulation and role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signaling, however, are largely unknown. Thus, the aim of our study was to characterize the expression and function of the Gαi-coupled adenosine A1-receptor in response to hypertrophic stimulation in vitro and in vivo.

Methods

Isolated rat cardiomyocytes were exposed to the α1-adrenergic receptor agonist phenylephrine (PE; 1-100 μM; 24h), to angiotensin II (AngII; 0.1-10 μM) or insulin-like growth factor (Igf-I; 0.2-20 ng/ml) and the expression of adenosine receptor subtypes was determined by PCR and Western blot analyses. The hypertrophic response was determined by cardiomyocyte cross sectional area (light microscopy), sarcomere organization (immunostaining of α–sarcomeric actinin), protein synthesis (3H-leucin-incorporation) and mRNA of the immediate early gene c-fos, in the absence and presence of the selective A1-receptor agonist CPA (N6-cyclopentyladenosine; 1 μM). C57Bl/6N mice were randomized to continuous PE-infusion (120 mg*kg*day) or vehicle (saline) for 21 days (osmotic mini-pumps) and cardiomyocyte cross sectional area, diameter and the amount of fibrosis analyzed by histology, respectively. Cardiac function in vivo was analyzed by echocardiography and MRI analyses.

Results

PE, but not AngII or Igf-I increased mRNA and protein expression of the A1-receptor in a concentration-dependent manner. A1-receptor stimulation reduced the PE-mediated increase in cardiomyocyte cross sectional area, the augmentation in sarcomeric organization, the rise in total protein expression as well as the increased expression of c-fos (p < 0.01, respectively). In contrast, CPA had no effects on the pro-hypertrophic effects of AngII or Igf-I. Accordingly, longterm PE-treatment in vivo upregulated A1-receptor protein expression. PE induced cardiomyocyte hypertrophy and fibrosis, which was blunted by co-treatment with CPA (PE: 14.1 ± 1.4%; PE + CPA: 3.3 ± 0.5%; p < 0.001).

Conclusion

α1-Adrenergic receptor stimulation leads to upregulation of the adenosine A1-receptor in vitro and in vivo, while stimulation of AngII- or Igf-I receptors has no such effect. Since A1-receptor stimulation counteracts PE-induced pro-hypertrophic and pro-fibrotic effects, this may resemble a distinct negative feedback mechanism regulating the myocardial maladaptive response induced by α-adrenergic receptor stimulation.

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