Spermidine ameliorates BK channel dysfunction in diabetic coronary smooth muscle cells via PKM2/STAT3/FBXO32 axis

  • Vascul Pharmacol. 2026 Jun 16:164:107672. doi: 10.1016/j.vph.2026.107672.
Zhen-Ye Zhang  1 ,  Jia-Bin Zhou  1 ,  Ya-Juan Yang  1 ,  Shan-Ying Zhao  1 ,  Si-Yu Fan  1 ,  Lu Pan  1 ,  Jun-Xian Shen  1 ,  Chao Wang  1 ,  Yang-Ge Shao  1 ,  Jie Zheng  1 ,  Ling-Ling Qian  2 ,  Shipeng Dang  3 ,  Ru-Xing Wang  4
Affiliations
  • 1. Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China.
  • 2. Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China. Electronic address: [email protected].
  • 3. Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China. Electronic address: [email protected].
  • 4. Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China. Electronic address: [email protected].
PMID: 42303097 DOI: 10.1016/j.vph.2026.107672
Abstract

Background: Spermidine (SPD) exhibits potential protective effects against diabetic-induced BK channel dysfunction, though the molecular mechanisms remain unclear. This study investigated SPD-mediated regulation of large-conductance calcium- and voltage-activated Potassium Channel (BK channel) function in coronary smooth muscle cells (SMCs) and the underlying molecular pathways.

Methods: Rats were randomly divided into: control (Ctrl), diabetes mellitus (DM), and DM with SPD treatment (DM + SPD) groups. Vascular function was assessed using coronary artery tension measurements, while BK channel activity was evaluated via whole-cell patch clamp. Primary vascular SMCs were isolated for in vitro studies. SPD-binding proteins were identified through pull-down assays coupled with LC-MS/MS analysis.

Results: SPD treatment improved coronary BK channel-dependent vasorelaxation by up-regulating BK-β1 subunit expression. Mechanistically, SPD directly bound to Pyruvate Kinase M2 (PKM2), inhibiting PKM2 nuclear translocation and subsequent signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, STAT3 transcriptionally regulated F-box protein 32 (FBXO32), which modulated BK-β1 expression.

Conclusions: SPD protects BK channel function in diabetic conditions through inhibition of the PKM2/STAT3 signaling axis, revealing a novel therapeutic pathway for diabetic vascular complications. However, given the exploratory experimental nature of this study, these findings should be considered hypothesis-generating and require further validation in independent studies.

Keywords
Diabetes mellitus; Large conductance calcium- and voltage-activated potassium channel; Pyruvate kinase isozyme type M2; Signal transducer and activator of transcription 3; Spermidine.
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