SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure.

Abstract (English)

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 (<i>Srebp1a</i>-Tg) and knockdown (Cre-<i>Srebf1</i>^f/f) mice were generated. AAV9 vectors carrying <i>Slc9a3</i> (encoding NHE3), <i>Srebp1a</i> or shRNA against <i>Slc9a3</i>, 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. <i>Srebp1a</i>-Tg mice exhibited impaired cardiac contractility with dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis identified increased NHE3 expression in <i>Srebp1a</i>-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 <i>SLC9A3</i> (encoding NHE3) by SREBP1. NHE3 activity was enhanced in cardiomyocytes isolated from <i>Srebp1a</i>-Tg mice or those underwent TAC, whereas cardiomyocyte-specific <i>Srebf1</i> knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of <i>Srebf1</i> or <i>Slc9a3</i> restored calcium handling and improved cardiac function in TAC mice. In <i>Srebp1a</i>-Tg mice, NHE3 knockdown alleviated Na⁺ and Ca²⁺ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-<i>Srebf1</i>^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.