Canagliflozin impairs blood reperfusion of ischaemic lower limb partially by inhibiting the retention and paracrine function of bone marrow derived mesenchymal stem cells
Yinuo Lin,
Jinliang Nan,
Jian Shen,
Xinhuang Lv,
Xiao Chen,
Xingmei Lu,
Chi Zhang,
Pingping Xiang,
Zhiting Wang,
Zhengzheng Li
Affiliations
Yinuo Lin
Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Jinliang Nan
Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Jian Shen
Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Xinhuang Lv
Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Xiao Chen
Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Xingmei Lu
Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
Chi Zhang
Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Pingping Xiang
Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Zhiting Wang
Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China; Co-corresponding author Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
Zhengzheng Li
Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China; Corresponding author.
Background: Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb. Methods: The in vivo blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed in vitro. In silico docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1). Findings: Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by in silico docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution). Interpretation: Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs. Funding: National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation. Keywords: Canagliflozin, Mesenchymal Stem Cells, Mitochondria, Glutamate dehydrogenase, Ischaemia
