Canagliflozin impairs blood reperfusion of ischaemic lower limb partially by inhibiting the retention and paracrine function of bone marrow derived mesenchymal stem cells

Abstract

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.

Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p

“…Our previous study also showed that MIF rejuvenates aged human MSCs and improves myocardial repair [ 12 ]. MSCs achieve cardiac protective function mainly through paracrine factors such as exosomes [ 20 – 23 ]. Recent studies have shown that exosomes derived from MSCs reduce myocardial ischemic injury and preserve cardiac function after MI [ 24 , 25 ].…”

Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p

“…through paracrine factors such as exosomes. [20][21][22][23] Recent studies have shown that exosomes derived from MSCs reduce myocardial ischemic injury and preserve cardiac function after MI. 24,25 Compared with conventional stem cell transplantation therapy, exosome therapy showed no teratoma development, minimum immunogenicity, and little potential for tumorigenesis.…”

Dapagliflozin Promotes Neovascularization by Improving Paracrine Function of Skeletal Muscle Cells in Diabetic Hindlimb Ischemia Mice Through PHD2/HIF-1α Axis

“…Recent studies have shown the protective effect of SGLT2 inhibitors (canagliflozin, empagliflozin, and dapagliflozin) against cardiovascular disease and death in patients with type 2 diabetes mellitus (Wiviott et al, 2019a;Arnott et al, 2020); however, oral admission of canagliflozin could increase the risk of limb amputation (Matthews et al, 2019), while both dapagliflozin and empagliflozin exhibit no evidence of risk (Dicembrini et al, 2019). Similarly, in vivo studies using diabetic HLI mice treated with orally administered canagliflozin results in a lower blood perfusion recovery compared to the control, while treatment with dapagliflozin results in a blood perfusion recovery comparable to that of the control (Lin et al, 2020).…”

“…Intriguingly, while dapagliflozin is known as an oral anti-hyperglycemic drug, we found that blood glucose levels of diabetic HLI mice do not change significantly after intramuscular injection of dapagliflozin. On the other hand, Lin et al showed that, compared to that of the control group, oral administration of dapagliflozin does not improve blood perfusion recovery in diabetic HLI mice ( Lin et al., 2020 ). Although the detailed mechanisms involved need to be investigated further, these distinct effects are most plausibly due to the difference in administration method.…”