SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure

Huijun Gu; Jianpei Wen; Yiyi Liu; Yanbo Xue; Mingming Zhao; Yifei Zhao; Lantian Bi; Hongtu Cui; Wenming Zhang; Xu Wenli; Kang Wang; Yawen Deng; Xiaoyue Yu; Haifan Wang; Jingui Hu; Wei Liu; Yuxuan Guo; Chen Chen; Erdan Dong; Youyi Zhang; John Y-J Shyy; Han Xiao

doi:10.1161/CIRCULATIONAHA.126.079823

SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure

Circulation. 2026 May 22. doi: 10.1161/CIRCULATIONAHA.126.079823. Online ahead of print.

Authors

Huijun Gu^{1

2}, Jianpei Wen³, Yiyi Liu¹, Yanbo Xue¹, Mingming Zhao¹, Yifei Zhao⁴, Lantian Bi¹, Hongtu Cui¹, Wenming Zhang¹, Xu Wenli^{1

5}, Kang Wang¹, Yawen Deng¹, Xiaoyue Yu¹, Haifan Wang¹, Jingui Hu¹, Wei Liu⁶, Yuxuan Guo⁷, Chen Chen³, Erdan Dong^{1

5

7}, Youyi Zhang¹, John Y-J Shyy⁸, Han Xiao^{1

5}

Affiliations

¹ 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.Z., H.X.).
² Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China (H.G.).
³ Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China (J.W., C.C.).
⁴ State Key Laboratory of Membrane Biology and Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China (Y.Z.).
⁵ NHC Key Laboratory of Cardiopulmonary Rehabilitation and Functional Recovery (University of Health and Rehabilitation Sciences), Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, China (W.X., E.D., H.X.).
⁶ Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK (W.L.).
⁷ School of Basic Medical Sciences, Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China (Y.G., E.D.).
⁸ Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, 92093 (J. Y.-J.S.).

PMID: 42170742
DOI: 10.1161/CIRCULATIONAHA.126.079823

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 Ca²⁺) 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-Srebp1^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 Srebp1 knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of Srebp1 or Slc9a3 restored calcium handling and improved cardiac function in TAC mice. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na⁺ and Ca²⁺ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebp1^f/f mice and controls, which offset the protective effect because of SREBP1 loss in the context of Na⁺ and Ca²⁺ 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.

Keywords: calcium; heart failure; myocardial contraction; sodium-hydrogen exchanger 3; sterol regulatory element-binding protein 1.