Heart failure & cardiomyopathies
SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure
Authors' conclusion
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.
Study context
- Population
- Heart failure with reduced ejection fraction (HFrEF) patients (dilated cardiomyopathy, without diabetes or hyperlipidemia) and transverse aortic constriction (TAC)-induced HFrEF mice
- Comparison
- Cardiomyocyte SREBP1 overexpression or knockdown, and NHE3 overexpression or knockdown, in HFrEF models
Methodological detailshuman cardiac tissue, TAC mouse model, cardiomyocyte-specific transgenic and knockdown mice, AAV9 gene transfer
- Human cardiac tissue
- TAC mouse model
- Cardiomyocyte-specific transgenic and knockdown mice
- AAV9 gene transfer
Main finding
As reported in the abstract
- SREBP1 activated in human HFrEF hearts (dilated cardiomyopathy, no diabetes or hyperlipidemia) and TAC-induced HFrEF mouse hearts
- Srebp1a-Tg mice: impaired cardiac contractility with dysregulated calcium handling, without apparent lipid accumulation
- Increased NHE3 expression in Srebp1a-Tg mice, TAC hearts and human failing hearts
- SREBP1 directly regulates SLC9A3 (NHE3) transcription (ChIP-seq, ChIP, promoter reporter assay)
- NHE3 activity increased in Srebp1a-Tg and TAC cardiomyocytes; reduced by cardiomyocyte Srebf1 knockdown in TAC mice
- Cardiomyocyte Srebf1 or Slc9a3 knockdown restored calcium handling and improved cardiac function in TAC mice
- In Srebp1a-Tg mice, NHE3 knockdown alleviated Na+ and Ca2+ overload and rescued systolic dysfunction
- NHE3 overexpression impaired contraction in Cre-Srebf1f/f and control mice, offsetting the protection of SREBP1 loss
Original publication
SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure. Circulation. Published 22 May 2026. doi:10.
Summarised from the published abstract; every number is checked against it