2. Academic Validation
  3. Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis

Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis

  • Cardiovasc Diabetol. 2024 Jul 23;23(1):269. doi: 10.1186/s12933-024-02366-0.
Ying Shi 1 2 3,  Lili Zhao 3,  Jing Wang 1,  Xiankun Liu 4,  Yiming Bai 4,  Hongliang Cong 5 6 7 8,  Ximing Li 9 10 11
Affiliations

Affiliations

  • 1 Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China.
  • 2 Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China.
  • 3 Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China.
  • 4 Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300222, China.
  • 5 Tianjin Chest Hospital, Tianjin Medical University, Tianjin, 300070, China. hongliangcong@163.com.
  • 6 Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China. hongliangcong@163.com.
  • 7 Tianjin Institute of Cardiovascular Disease, Tianjin Chest Hospital, Tianjin, 300222, China. hongliangcong@163.com.
  • 8 Department of Cardiology, Tianjin Chest Hospital, Tianjin, 300222, China. hongliangcong@163.com.
  • 9 Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, 300222, China. ljsunlight@126.com.
  • 10 Chest Hospital, Tianjin University, Tianjin, 300072, China. ljsunlight@126.com.
  • 11 Department of Cardiology, Tianjin Chest Hospital, Tianjin, 300222, China. ljsunlight@126.com.
PMID: 39044275 DOI: 10.1186/s12933-024-02366-0
Abstract

Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.

Keywords

Empagliflozin; Heart failure; STAT1; STING; Senescence.

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