Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice
Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice
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DOI：
10.1038/s41598-020-70956-5
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发表时间：
2020-08-18
影响因子：
4.6
通讯作者：
Nishida, Motohiro
中科院分区：
文献类型：
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作者：
Shimoda, Kakeru;Nishimura, Akiyuki;Nishida, Motohiro
血流动力学超负荷引起的心脏组织重构是心力衰竭的主要临床结局。尿苷反应性嘌呤能P2Y（6）受体（P2Y（6）R）参与啮齿类动物心血管重构的进展，但目前尚不清楚抑制P2Y（6）R是否预防或促进心力衰竭。我们证明，抑制P2Y（6）R促进压力超负荷诱导的小鼠猝死和心力衰竭。在新生心肌细胞中，P2Y（6）R的敲低显著减弱了由低渗刺激引起的肥大生长和细胞死亡，表明P2Y（6）R参与了机械应激诱导的心肌功能障碍。出乎意料的是，与野生型小鼠相比，P2Y（6）R的缺失促进了压力超负荷诱导的猝死，以及心脏重塑和功能障碍。心肌细胞特异性过表达P2Y（6）R的小鼠也表现出心脏功能障碍和严重的纤维化。相比之下，P2Y（6）R缺失对阿霉素治疗诱导的氧化应激介导的心功能障碍影响不大。这些发现提供了压倒性的证据，即全身抑制P2Y（6）R会加剧小鼠压力超负荷诱导的心力衰竭，尽管心肌细胞中的P2Y（6）R有助于心脏纤维化的进展。
Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y(6) receptor (P2Y(6)R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y(6)R prevents or promotes heart failure. We demonstrate that inhibition of P2Y(6)R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y(6)R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y(6)R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y(6)R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y(6)R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y(6)R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y(6)R exacerbates pressure overloadinduced heart failure in mice, although P2Y(6)R in cardiomyocytes contributes to the progression of cardiac fibrosis.