Treatment of Heart Failure by a Methanocarba Derivative of Adenosine Monophosphate: Implication for a Role of Cardiac Purinergic P2X Receptors

Abstract

Evidence is accumulating to support a potentially important role for purinergic (P2X) receptors in heart failure (HF). We tested the hypothesis that a hydrolysis-resistant nucleotide analog with agonist activity at myocardial P2X receptors (P2XRs) improves the systolic HF phenotype in mouse and dog models. We developed a hydrolysis-resistant adenosine monophosphate derivative, (1ЈS,2R,3S,4ЈR,5ЈS)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicycle[3.1.0]hexane-2,3-diol) (MRS2339), with agonist activity at native cardiac P2XRs. Chronic MRS2339 infusion in postinfarct and calsequestrin (CSQ) mice with HF resulted in higher rates of pressure change (ϩdP/dt), left ventricle (LV)-developed pressure, and cardiac output in an in vitro working heart model. Heart function in vivo, as determined by echocardiography-derived fractional shortening, was also improved in MRS2339-infused mice. The beneficial effect of MRS2339 was dose-dependent and was identical to that produced by cardiac myocyte-specific overexpression of the P2X 4 receptor. The HF improvement was associated with the preservation of LV wall thickness in both systole and diastole in postinfarct and CSQ mice. In dogs with pacing-induced HF, MRS2339 infusion reduced left ventricular end-diastolic pressure, improved arterial oxygenation, and increased ϩdP/dt. MRS2339 treatment also decreased LV chamber size in mice and dogs with HF. In murine and canine models of systolic HF, in vivo administration of a P2X nucleotide agonist improved contractile function and cardiac performance. These actions were associated with preserved LV wall thickness and decreased LV remodeling. The data are consistent with a role of cardiac P2XRs in mediating the beneficial effect of this agonist.Interest has grown in the physiological role of purinergic (P2) receptors for extracellular ATP within the cardiovascular system. There are two subfamilies of P2 receptors: ligandgated ion channel and G protein-coupled receptors, termed P2X and P2Y, respectively (North, 2002;Abbracchio et al., 2006). Seven subtypes of P2X (P2X 1 -7 ) receptors have been identified by molecular cloning. The various cloned P2Y receptors are coupled to phospholipase C (PLC) (for P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 ), PLC and Gs (for P2Y 11 ) (Communi et al., 1997;Hollopeter et al., 2001;Zhang et al., 2001), and G i (P2Y 12 , P2Y 13 , P2Y 14 ). Members of both the P2X and P2Y families are expressed in the heart (Erlinge and Burnstock, 2008). P2X 1 receptor expression is increased in the left atria of patients with dilated cardiomyopathy (Berry et al., 1999), whereas the P2Y 11 receptor is present in all four chambers of the heart (Communi et al., 1997).In the heart, extracellular ATP can elicit an increase in

AMP Is an Adenosine A1 Receptor Agonist

“…We found that a non-hydrolyzable phosphonate analog of AMP could activate hA 1 R. Interestingly, other ectonucleotidase-resistant phosphonate analogs of AMP reportedly activate P2X receptors and have cardioprotective activity in vivo (47,48). Although it was suggested that the cardioprotective effects of these AMP analogs were due to P2X activation, P2X involvement was never directly tested in vivo with antagonists or knock-out mice.…”

Cardiac purinergic signalling in health and disease

“…P2XR activation protected the heart in heart failure models [481,482]. A beneficial effect of MRS2339, a P2XR agonist in heart failure was demonstrated; it was identical to that produced by cardiac myocyte-specific over-expression of the P2X4R [483]. The improvement was associated with the preservation of left ventricular wall thickness in both systole and diastole in post-infarct mice and calsequestrin (CSQ) over-expression mice with cardiac-specific P2X4R overexpression and decreased left ventricular chamber size in CSQ mice with heart failure and dogs with pacing-induced heart failure [483].…”

“…UTP, but not ATP, caused hypertrophic growth in neonatal cardiomyocytes [736]. Overexpression of human P2X4R in ventricular myocytes of a transgenic mouse increased basal cardiac contractility without cardiac hypertrophy or failure [274] and activation with a P2X4R agonist had beneficial effects [483]. Deletion of the P2Y4R gene in mice lowered exercise capacity and reduced myocardial hypertrophy [737].…”

Activation and Regulation of Purinergic P2X Receptor Channels

“…Experiments that measure the displacement of [ 35 S]ATP␥S from rP2X4Rs also indicated that ATP is the most potent agonist, followed by ATP␥S, 2-meSATP, and ␣␤-meATP . A methanocarba derivative of AMP, 1ЈS,2R,3S,4ЈR,5ЈS)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicycle[3.1.0]hexane-2,3-diol) (MRS2339), has been found to act as a potent agonist of heart purinergic receptors; the authors suggested that this compound could be a P2X4R agonist (Zhou et al, 2010).…”