Loss of Mouse P2Y6 Nucleotide Receptor Is Associated with Physiological Macrocardia and Amplified Pathological Cardiac Hypertrophy

Abstract

The study of the mechanisms leading to cardiac hypertrophy is essential to better understand cardiac development and regeneration. Pathological conditions such as ischemia or pressure overload can induce a release of extracellular nucleotides within the heart. We recently investigated the potential role of nucleotide P2Y receptors in cardiac development. We showed that adult P2Y 4 -null mice displayed microcardia resulting from defective cardiac angiogenesis. Here we show that loss of another P2Y subtype called P2Y 6 , a UDP receptor, was associated with a macrocardia phenotype and amplified pathological cardiac hypertrophy. Cardiomyocyte proliferation and size were increased in vivo in hearts of P2Y 6 -null neonates, resulting in enhanced postnatal heart growth. We then observed that loss of P2Y 6 receptor enhanced pathological cardiac hypertrophy induced after isoproterenol injection. We identified an inhibitory effect of UDP on in vitro isoproterenol-induced cardiomyocyte hyperplasia and hypertrophy. The present study identifies mouse P2Y 6 receptor as a regulator of cardiac development and cardiomyocyte function. P2Y 6 receptor could constitute a therapeutic target to regulate cardiac hypertrophy.Cardiovascular pathologies are the main cause of mortality in developed countries. Heart failure is characterized by cardiac hypertrophy and fibrosis. Pathological cardiac hypertrophy can be caused inter alia by hypertension, myocardial infarct, or diabetes and is associated with cardiac cell death, cardiomyocyte hypertrophy, and increased proliferation of cardiac fibroblasts.The role of P2Y nucleotide receptors in the heart has not been extensively studied. Cardioprotective effect of UTP has been previously described: treatment with UTP prior to myocardial infarction leads to reduced ischemic damage through P2Y 2 receptor activation (1, 2). Another UTP receptor, P2Y 4 , plays an important role in the heart: P2Y 4 knock-out (KO) mice display reduced cardiac angiogenesis and cardiac postnatal development (3), as well as lower exercise capacity and reduced exercise-induced cardiac hypertrophy (4). More recently, it has been shown that P2Y 4 KO mice display lower infarct size and reduced cardiac inflammation and fibrosis in a model of ligation of the left anterior descending artery (5). The study of the role of P2Y 6 UDP receptor in the heart has also been initiated. UDP can have an inotropic effect on cardiomyocytes, mediated by P2Y 6 receptor (6). Nishida et al. (7) showed that inhibition of P2Y 6 receptor using the specific antagonist MRS2578 decreased collagen deposition after transverse aortic constriction, without affecting cardiac hypertrophy induced in this model. Also, P2Y 6 receptor seems to have a deleterious role in atherosclerosis, being enriched in the sclerotic lesions and favoring inflammation (8, 9). These various effects of nucleotides are depending on cell-specific expression of P2Y subtypes involved: mouse P2Y 4 receptor is not expressed in cardiomyocytes and is mainly expressed in cardiac endotheli...

Purinergic Signaling in the Cardiovascular System

“…119 It has been suggested that P2Y 6 receptors could constitute a therapeutic target to regulate cardiac hypertrophy. 120 A 2B receptor activation exerts stronger cardioprotective effects against cardiac ischemia/ reperfusion injury compared with A 2A receptor activation in rats.…”

Purinergic dysregulation causes hypertensive glaucoma–like optic neuropathy

“…Transepithelial Cl -transport across the ciliary epithelium was reported to produce the driving force for aqueous humor formation (45)(46)(47)(48)(49)(50). Cl -secretion from NPE cells is mediated by Cl -channels, whose activity is controlled by intracellular cyclic adenosine monophosphate (cAMP), which is increased by P2Y 6 receptor activation (51,52). It has been reported that cAMP causes both an increase (52-54) and decrease of Cl -secretion (55)(56)(57).…”

Purinergic Signalling: Therapeutic Developments

“…P2YR are important therapeutic targets in myocardial protection during ischemia/reperfusion ( Djerada et al, 2017 ). P2Y 6 R could be a therapeutic target to regulate cardiac hypertrophy ( Clouet et al, 2016 ). There is increased expression of P2Y 2 and P2X1R in the hearts of rats with congestive heart failure.…”