Deficiency of PKD2L1 (TRPP3) Exacerbates Pathological Cardiac Hypertrophy by Augmenting NCX1-Mediated Mitochondrial Calcium Overload
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
Affiliations
Zongshi Lu
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Yuanting Cui
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Xing Wei
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Peng Gao
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China; Corresponding author
Hexuan Zhang
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Xiao Wei
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Qiang Li
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Fang Sun
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Zhencheng Yan
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Hongting Zheng
Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
Gangyi Yang
Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, Chongqing 400010, China
Daoyan Liu
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
Zhiming Zhu
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China; Corresponding author
Summary: 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. : Lu et al. reveal a role of a mitochondria-localized TRPP member, PKD2L1, in high salt-induced cardiac hypertrophy. PKD2L1 knockout leads to overexpression of NCX1 through increasing the acetylation level of histone 3 lysine 27 on NCX1 promoter and thus exacerbates mitochondrial calcium overload by activating the reverse mode of NCX1 in cardiomyocytes. Keywords: high-salt diet, cardiac hypertrophy, PKD2L1, mitochondria, NCX1
