Inhibition of Phenylephrine-Induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes

Abstract

Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 M) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A 1 receptor agonist N 6 -cyclopentyladenosine (1 M), the A 2A receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5Ј-N-ethylcarboxamidoadenosine (100 nM), and the A 3 receptor agonist N 6 -(3-iodobenzyl)adenosine-5Ј-methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.

Interference with ERK Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

“…1B and quantification of cell size in Fig. S1E) (16,17). Strikingly, ERK2 T188A did not enhance H 2 O 2 -induced apoptotic cell death, as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) (Fig.…”

Long-Term Stimulation of Adenosine A2b Receptors Begun After Myocardial Infarction Prevents Cardiac Remodeling in Rats

“…40 We have recently demonstrated that adenosine inhibits cardiac hypertrophy through adenosine A1 receptor in pressure-overloaded hearts. 15 Interestingly, we found that either DIP or CADO attenuated hypertrophic changes in cardiomyocytes and mRNA levels of ANF and BNP in the noninfarcted LV, both of which were blunted by DPCPX, the antagonist of adenosine A1 receptors.…”

Cardiac purinergic signalling in health and disease

“…Phenylephrine-induced cardiomyocyte hypertrophy in rats was inhibited by activation of multiple adenosine receptor subtypes [731]. In addition, hypertrophy induced by phenylephrine in cultured rat ventricular myocytes was associated with compensatory up-regulation of the adenosine system manifested in the significant increase in gene and protein expression of adenosine A1R, A2AR and A3R [732], furthermore, phenylephrine-induced cardiomyocyte hypertrophy and calcification were shown to be regulated by the interaction of CD73 and alkaline phosphatase and inhibited by adenosine receptor activation [733].…”