Your browser doesn't support javascript.
loading
Canagliflozin impairs blood reperfusion of ischaemic lower limb partially by inhibiting the retention and paracrine function of bone marrow derived mesenchymal stem cells.
Lin, Yinuo; Nan, Jinliang; Shen, Jian; Lv, Xinhuang; Chen, Xiao; Lu, Xingmei; Zhang, Chi; Xiang, Pingping; Wang, Zhiting; Li, Zhengzheng.
Afiliación
  • Lin Y; Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
  • Nan J; Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
  • Shen J; Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
  • Lv X; Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
  • Chen X; Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
  • Lu X; Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
  • Zhang C; Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
  • Xiang P; Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
  • Wang Z; Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China. Electronic address: wzt665523@sina.com.
  • Li Z; Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China. Electronic address: Leezz2005@126.com.
EBioMedicine ; 52: 102637, 2020 Feb.
Article en En | MEDLINE | ID: mdl-31981975
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.

FUNDING:

National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 6_ODS3_enfermedades_notrasmisibles Problema de salud: 6_cardiovascular_diseases / 6_other_malignant_neoplasms Asunto principal: Daño por Reperfusión / Comunicación Paracrina / Células Madre Mesenquimatosas / Canagliflozina / Inhibidores del Cotransportador de Sodio-Glucosa 2 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: EBioMedicine Año: 2020 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 6_ODS3_enfermedades_notrasmisibles Problema de salud: 6_cardiovascular_diseases / 6_other_malignant_neoplasms Asunto principal: Daño por Reperfusión / Comunicación Paracrina / Células Madre Mesenquimatosas / Canagliflozina / Inhibidores del Cotransportador de Sodio-Glucosa 2 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: EBioMedicine Año: 2020 Tipo del documento: Article País de afiliación: China
...