RESUMEN
BACKGROUND AND AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms. METHODS: Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry. RESULTS: Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group. CONCLUSIONS: Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.
RESUMEN
Este trabajo es el octavo de una serie dedicada a los procedimientos de referencia para la medición de las concentraciones de actividad catalítica de las enzimas a 37 ºC y a la certificación de las preparaciones de referencia. Otras partes se refieren a: Parte 1. El concepto de los procedimientos de referencia para la medición de las concentraciones de la actividad catalítica de las enzimas; Parte 2. Procedimiento de referencia para la medición de la concentración catalítica de creatina quinasa; Parte 3: Procedimiento de referencia para la medición de la concentración catalítica de lactato deshidrogenasa; Parte 4. Procedimiento de referencia para la medición de la concentración catalítica de alanin aminotransferasa; Parte 5. Procedimiento de referencia para la medición de la concentración catalítica de aspartato aminotransferasa; Parte 6. Procedimiento de referencia para la medición de la concentración catalítica de gamma-glutamiltransferasa; Parte 7. Certificación de cuatro materiales de referencia para la determinación de la actividad enzimática de gamma-glutamiltransferasa, lactato deshidrogenasa, alanin aminotransferasa y creatina quinasa a 37 ºC. El procedimiento que se describe aquí se deduce a partir del método de referencia de la IFCC a 30 ºC descrito previamente. Las diferencias se tabulan y comentan en Clin Chem Lab Med 2006; 44: 1146-55.