SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure
Abstract
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion (ie, Na + /H + and Ca 2+ ) cycling underlies reduced cardiac contractility. The mechanisms linking myocardial stress to this ion dysregulation remain incompletely understood. Although the metabolic transcription factor SREBP1 (sterol regulatory element-binding protein 1) remodels cardiac metabolism, its role in HFrEF without metabolic comorbidities, particularly regarding ion handling, remains undefined. METHODS: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for SREBP1 transactivation of sodium-hydrogen exchanger 3 (NHE3). Cardiomyocyte-specific SREBP1 transgenic ( Srebp1a -Tg) and knockdown (Cre- Srebf1 f/f ) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebp1a or shRNA against Slc9a3 , driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. RESULTS: SREBP1 was activated in human hearts with HFrEF because of dilated cardiomyopathy, but without diabetes or hyperlipidemia, and in TAC-induced HFrEF mouse hearts. Srebp1a -Tg mice exhibited impaired cardiac contractility with dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis identified increased NHE3 expression in Srebp1a -Tg mice, confirmed by NHE3 upregulation in TAC hearts and human failing hearts. ChIP-seq, ChIP, and promoter reporter assay demonstrated direct transcriptional regulation of SLC9A3 (encoding NHE3) by SREBP1. NHE3 activity was enhanced in cardiomyocytes isolated from Srebp1a -Tg mice or those underwent TAC, whereas cardiomyocyte-specific Srebf1 knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of Srebf1 or Slc9a3 restored calcium handling and improved cardiac function in TAC mice. In Srebp1a -Tg mice, NHE3 knockdown alleviated Na + and Ca 2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre- Srebf1 f/f mice and controls, which offset the protective effect because of SREBP1 loss in the context of Na + and Ca 2+ overload. CONCLUSIONS: SREBP1 directly transactivates cardiac NHE3 during the progression of HFrEF, leading to dysregulated calcium handling and impaired contractility, revealing a novel, noncanonical role for SREBP1 in the pathophysiology of heart failure and offering a potential new therapeutic target.
Article Details
Authors (22)
Huijun Gu
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Jianpei Wen
Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China (J.W., C.C.).
Yiyi Liu
Yanbo Xue
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Mingming Zhao
Yifei Zhao
Lantian Bi
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Hongtu Cui
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Wenming Zhang
State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University
Wenli Xu
Hubei Key Laboratory of Intelligent Vision Based Monitoring For Hydroelectric Engineering College of Materials and Chemical Engineering China Three Gorges University Yichang China
Kang Wang
Yawen Deng
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Xiaoyue Yu
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Haifan Wang
Jingui Hu
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Wei Liu
Yuxuan Guo
National Key Laboratory of Innovative Immunotherapy, Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences
Chen Chen
Erdan Dong
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
Youyi Zhang
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Advanced Clinical Medicine, Peking University; National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing 100191, China (H.G., Y.L., Y.X., M.Z., L.B., H.C., W.Z., W.X., K.W., Y.D., X.Y., H.W., J.H., E.D., Y. Zhang, H.X.).
John Y.-J. Shyy
Han Xiao
Department of Chemistry, Rice University, 6100 Main Street, Houston, Texas 77005, United States