Loss of mouse P2Y6 nucleotide receptor is associated with physiological macrocardia and amplified pathological cardiac hypertrophy

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 P2Y4-null mice displayed microcardia 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 post-natal heart growth. We then observed that loss of P2Y6 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 P2Y6 receptor as a regulator of cardiac development and cardiomyocyte function. P2Y6 receptor could constitute a therapeutic target to regulate cardiac hypertrophy.阐明导致心肌肥厚（cardiac hypertrophy）的分子机制，对于深入理解心脏发育与再生过程至关重要。诸如缺血（ischemia）或压力负荷（pressure overload）等病理状态，可诱导心脏内释放细胞外核苷酸。本团队此前已探究了核苷酸P2Y受体（P2Y receptor）在心脏发育中的潜在作用，研究显示成年P2Y4基因敲除小鼠会因心脏血管生成缺陷而表现出心小症表型。 本研究证实，另一种名为P2Y6的P2Y受体亚型——UDP受体——的缺失，与心大症表型及加剧的病理性心肌肥厚相关。在P2Y6基因敲除新生小鼠的活体心脏中，心肌细胞增殖活性与细胞体积均有所增加，进而促进出生后心脏的生长。随后我们观察到，P2Y6受体的缺失会加重异丙肾上腺素（isoproterenol）注射诱导的病理性心肌肥厚。本研究还明确了UDP对体外环境中异丙肾上腺素诱导的心肌细胞增生与肥厚的抑制作用。 本研究确定小鼠P2Y6受体为心脏发育及心肌细胞功能的调控因子，P2Y6受体可作为调控心肌肥厚的治疗靶点。