Deficiency of PKD2L1 (TRPP3) Exacerbates Pathological Cardiac Hypertrophy by Augmenting NCX1-Mediated Mitochondrial Calcium Overload.

Abstract

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.

• Authors: Zongshi Lu, Yuanting Cui, Xing Wei, Peng Gao, Hexuan Zhang, Xiao Wei, Qiang Li, Fang Sun, Zhencheng Yan, Hongting Zheng, Gangyi Yang, Daoyan Liu, Zhiming Zhu
• Journal: Cell reports (Cell Rep) Vol. 24 Issue 6 Pg. 1639-1652 (08 07 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30089272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channels
• Histones
• NCX1 protein, mouse
• Pkd2l1 protein, mouse
• Receptors, Cell Surface
• Sodium-Calcium Exchanger
• Calcium

Topics

• Acetylation
• Animals
• Calcium (metabolism)
• Calcium Channels (deficiency, genetics, metabolism)
• Calcium Signaling
• Cardiomegaly (genetics, metabolism, pathology)
• Disease Models, Animal
• Gene Knockout Techniques
• Histones (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria, Heart (metabolism, pathology)
• Myocytes, Cardiac (metabolism)
• Rats
• Receptors, Cell Surface (deficiency, genetics, metabolism)
• Sodium-Calcium Exchanger (genetics, metabolism)
• Up-Regulation