Loss of Mouse P2Y 6 Nucleotide Receptor Is Associated with Physiological Macrocardia and Amplified Pathological Cardiac Hypertrophy

The study of the mechanisms leading to cardiac hypertro- phy 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 develop- ment.Weshowed that adult P2Y4-null mice displayed micro- cardia resulting from defective cardiac angiogenesis. Here we show that loss of another P2Y subtype called P2Y6, 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 P2Y6-null neonates, resulting in enhanced postnatal heart growth. We then observed that loss of P2Y6 receptor enhanced pathological cardiac hypertrophy induced after isoproterenol injection. We identified an inhibitory effect of UDPon in vitro isoproterenol-induced cardiomyocyte hyper- plasia and hypertrophy. The present study identifies mouse P2Y6 receptor as a regulator of cardiac development and car- diomyocyte function. P2Y6 receptor could constitute a ther- apeutic target to regulate cardiac hypertrophy.