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Published on: September 18, 2017
Spermidine ameliorates BK channel dysfunction in diabetic coronary smooth muscle cells via PKM2/STAT3/FBXO32 axis
Zhen-Ye Zhang1, Jia-Bin Zhou1, Ya-Juan Yang1
1Department 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.
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.
