A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to α1 ­ adrenergic stimulation in vivo . PubMed Commons

Puhl Sl, A Kazakov, A Müller, P Fries, M Böhm, C Maack, Y Devaux
Br J Pharmacol2015
BACKGROUND AND PURPOSE: Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of the A1 receptor in response to hypertrophic stimulation in vitro and in vivo. EXPERIMENTAL APPROACH: Pro-hypertrophic/A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, subcutaneous drug administration, RT-PCR, 3 [H]-leucine-incorporation assay, immunostaining, tissue staining, western-blot, gravimetric analyses and echocardiography were applied in this study. KEY RESULTS: In isolated neonatal rat cardiomyocytes, phenylephrine up-regulated the A1 receptor in a concentration-dependent manner, while angiotensinII and insulin-like growth factor I had no such effect. The selective A1 receptor agonist N6-cyclopentyladenosine counteracted the phenylephrine (10 μM), but not the angiotensinII (1 μM) or insulin-like growth factor I (20 ng ml-1 ) mediated hypertrophic phenotype (cardiomyocyte size, sarcomeric organization, total protein synthesis, c-fos expression; p<0.01). In C57/BL6 mice, continuous N6-cyclopentyladenosine infusion (2 mg kg-1 day-1 ; 21 days) blunted phenylephrine (120 mg kg-1 day-1 ; 21 days) induced hypertrophy (heart weight, cardiomyocyte size, foetal genes), fibrosis, matrix metalloproteinase 2 up-regulation and generation of oxidative stress - all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased A1 receptor expression. CONCLUSIONS & IMPLICATIONS: Our data allude to a negative feedback mechanism attenuating pathological hypertrophy following α1 -adrenoceptor stimulation and thereby suggest the A1 receptor as a potential target for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure-overload. This article is protected by copyright. All rights reserved.
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