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Contribucin de la disfuncin mitocondrial al desarrollo de las complicaciones vasculares de la Diabetes Tipo 2 Mara Monsalve mpmonsalve@iib.uam.es Vascular complications of diabetes Diabetic retinopathy Leakage Loss of pericytes

  1. Contribución de la disfunción mitocondrial al desarrollo de las complicaciones vasculares de la Diabetes Tipo 2 María Monsalve mpmonsalve@iib.uam.es

  2. Vascular complications of diabetes

  4. Diabetic retinopathy Leakage Loss of pericytes Hemorrhages Tortuosity

  5. Clinical treatment, anti-VEGF -Inefective angiogenesis, -Vessels are tortuous, dilated, poorly perfused -Poor perycite coverage -Hemorragic -Tissular hypoxia

  8. Hyperglicemia Increases mitochondrial ROS production [gluc] 5mM 30mM PGC-1  PGC-1 a � I.Valle et al. , CvR, 2005 MitoSox S. Borniquel et al. , MCB, 2010

  9. Mitocondria, una fuente de ROS Cu-ZnSOD O 2.- H 2 O 2 ETC Intermembrane space H + H + H + O 2 .- CoQ C UC ATPasa P Iinner I F 1 Mitochondrial III IV NADH Membrane F 0 II NADPH DH O 2 H 2 O ADP ATP O 2 .- NADP + O 2 .- P i NADH FADH 2 H + H + GR Mitochondrial matrix GSH PGC-1  GSSG ROS MnSOD GPx ROS ANTIOXIDANT Production ANTIOXIDANT O 2.- H 2 O 2 H 2 O + O 2 PRODUCTION DEFENCES DEFENCES Physiopathologica ONOO - l conditions NADPH CAT NADP + TrxS 2 H 2 O + O 2 TrxR OXIDATIVE STRESS HOMEOSTASIS Fenton reaction Prx Cellular damage Signalling Trx(SH) 2 Diseases . OH Cell death Aging H 2 O

  10. PGC-1  , a modulator of mitochondrial ROS Glucose ATP ATP Glucose ROS ATP Glucose ROS PGC-1  PGC-1  ATP ATP Lipids ROS 160 Mitochondria PGC-1 � RNA-POL� II � 120 * % 80 TF � * 40 0 5 mM Gluc 30 mM Gluc 48 h treatment Control Ad- PGC- 1 Ad I.Valle et al. , CvR, 2005

  11. Perdida de recubrimiento pericítico y baja perfusión en ausencia de PGC-1  PGC-1  +/+ PGC-1! +/+ PGC-1 α +/+ PGC-1 α -/- Isolectin B4 NG2 SMA PGC-1  -/- PGC-1! -/- PGC-1 α +/+ PGC-1 α -/- PGC-1! +/+ PGC-1! -/- Isolectin B4 NG2 SMA PGC-1 a � +/+� PGC-1 a � *� -/-� Mean Intensity Area 35 18 40 10 16 30 8 30 14 a.u. % ! Area (%) Area (%) *� 25 % 12 6 % ! %� 20 20 10 4 8 15 *� 10 6 2 10 4 0 0 5 2 PGC-1 ! ! "#"! PGC-1 ! ! $ PGC-1 ! ! PGC-1 ! ! $ #$ ! "#"! #$ ! 0 0 Iso B4 SMA NG2/edge NG2/center N. García-Quintans et al. , Angiogénesis, 2016

  12. OIR induce la translocación de VE-Cadherin al citosol en ausencia de PGC-1  PGC-1 α +/+ PGC-1 α -/- 1E+11 OIR 9E+10 Membrane 8E+10 Cytosol 7E+10 6E+10 5E+10 4E+10 3E+10 *� 2E+10 1E+10 0 PGC-1 a � PGC-1 a � +/+� -/-� N. García-Quintans et al. , Angiogénesis, 2016

  13. Torduosidad y hemorragias en ausencia de PGC-1  PGC- PGC- PGC-1 α +/+ PGC-1 α -/- 1 α +/+ 1 α -/- Primary plexus D SD* PGC-1 a +/+ PGC-1 a -/- PGC-1 a +/+ PGC-1 a -/- PGC-1 a +/+ PGC-1 a -/- PGC-1 α +/+ PGC-1 α -/- Number of Hemorrhages % ! 80 25! Hemorrhage Area % ! 20! 60 15! 40 10! 20 5! 0 0! PGC-1 ! ! "#"! PGC-1 ! ! PGC-1 ! ! "#"! PGC-1 ! ! $ #$ ! $ #$ ! N. García-Quintans et al. , Angiogénesis, 2016

  14. Antioxidant treatment improves vascular stability OIR PGC-1 α -/- OIR PGC-1 α -/- V � Iso B4 NG2 EUK-189 Primary plexus Inner plexus PGC-1 a � +/+� PGC-1 a � -/-� Area (%) Vehicle EUK-189 Vehicle EUK-189 Primary plexus *� D SD* Iso B4 NG2 SMA Vehicle EUK-189 Vehicle EUK-189 N. García-Quintans et al. , Angiogénesis, 2016

  15. El tratamiento con antioxidantes no recupera la polaridad de las células tip PGC-1 α +/+ PGC-1 α -/- PGC-1 α +/+ Iso B4 PGC-1 α -/- EUK-189 V Iso B4 N. García-Quintans et al. , Angiogénesis, 2016

  16. IPC induces perivascular fibrosis in the absence of PGC-1 α C. Sánchez-Ramos et al. , ARS, 2017

  17. MEMORY Prevalence of mitochondrial dysfunction in T2D -The mtDNA

  19. ¿Quiénes somos? El lab: Ignacio Prieto Raquel García Principales colaboradores: Gaurang Patel Ramazan Yildiz Ángela M Valverde (IIBm) Sebastian Cerdán (IIBm) Isabel Cordova Susana Cadenas (CBMSO) Miriam Granado (UAM) Jose Carlos Martinez Santamaría

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