Deficiency of PKD2L1 (TRPP3) Exacerbates Pathological Cardiac Hypertrophy by Augmenting NCX1-Mediated Mitochondrial Calcium Overload
Deficiency of PKD2L1 (TRPP3) Exacerbates Pathological Cardiac Hypertrophy by Augmenting NCX1-Mediated Mitochondrial Calcium Overload
复制标题
PKD2L1 (TRPP3) 缺乏会增加 NCX1 介导的线粒体钙超载，从而加剧病理性心脏肥大
DOI：
10.1016/j.celrep.2018.07.022
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发表时间：
2018-08-07
期刊：
影响因子：
8.8
通讯作者：
Zhu, Zhiming
中科院分区：
文献类型：
--
作者：
Lu, Zongshi;Cui, Yuanting;Zhu, Zhiming
高盐摄入是心脏肥大的一个独立危险因素。多囊肾病2样蛋白1（PKD 2L 1，也称为TRPP 3）在味觉细胞中充当酸味传感器，其在心血管系统中的可能作用尚不清楚。在这里，我们报告说，PKD 2L 1基因敲除加剧了高盐饮食（HSD）诱导的心脏肥大和纤维化，伴随着心功能障碍，减少心脏线粒体氧化磷酸化和酶活性。此外，PKD 2L 1的敲低导致更严重的线粒体Ca 2+超载和高盐负荷心肌细胞的Ca 2+摄取减少。在机制上，PKD 2L 1缺陷通过抑制AMP活化蛋白激酶（AMPK）活性增加了p300介导的钠/钙交换1（NCX 1）启动子上组蛋白3赖氨酸27的乙酰化，导致NCX 1过表达和线粒体Ca 2+超载。这些结果揭示了PKD 2L 1对心肌肥大的抑制作用，并提供了线粒体Ca 2+稳态和心肌肥大之间的联系的机制的见解。
High salt intake is one independent risk factor for cardiac hypertrophy. Polycystic kidney disease 2-like 1 (PKD2L1, also called TRPP3) acts as a sour sensor in taste cells, and its possible role in the cardiovascular system is unknown. Here, we report that knockout of PKD2L1 exacerbated high-salt diet (HSD)-induced cardiac hypertrophy and fibrosis, accompanied by cardiac dysfunction and reduced cardiac mitochondrial oxidative phosphorylation and enzyme activity. Furthermore, knockdown of PKD2L1 led to more serious mitochondrial Ca2+ overload and reduced Ca2+ uptake in cardiomyocytes on high salt loading. Mechanistically, PKD2L1 deficiency increased p300-mediated acetylation of histone 3 lysine 27 on the promoter of sodium/calcium exchange 1 (NCX1) by repressing AMP-activated protein kinase (AMPK) activity, resulting in NCX1 overexpression and mitochondrial Ca2+ overload. These results reveal an inhibitory effect of PKD2L1 on cardiac hypertrophy and provide a mechanistic insight into the link between mitochondrial Ca2+ homeostasis and cardiac hypertrophy.