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Contribucin de la disfuncin mitocondrial al desarrollo de las - - PowerPoint PPT Presentation
Contribucin de la disfuncin mitocondrial al desarrollo de las - - PowerPoint PPT Presentation
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
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Diabetic retinopathy
Leakage Loss of pericytes Hemorrhages Tortuosity
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Clinical treatment, anti-VEGF
- Inefective angiogenesis,
- Vessels are tortuous, dilated, poorly perfused
- Poor perycite coverage
- Hemorragic
- Tissular hypoxia
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Hyperglicemia Increases mitochondrial ROS production
MitoSox
PGC-1
I.Valle et al., CvR, 2005
- S. Borniquel et al., MCB, 2010
[gluc] 5mM 30mM PGC-1a
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C I NADH CoQ II DH IV ATPasa UC P ADP ATP O2 H2O H+ H+ O2.- O2.- O2.- H+ H+ H+ NADH FADH2
F1 F0
Pi III Intermembrane space Iinner Mitochondrial Membrane
Mitochondrial matrix
ETC
ROS PRODUCTION ANTIOXIDANT DEFENCES
HOMEOSTASIS OXIDATIVE STRESS
ROS Production ANTIOXIDANT DEFENCES Cellular damage Signalling Cell death Diseases Aging Physiopathologica l conditions
O2.-
H2O2 Cu-ZnSOD NADPH H2O
O2.-
H2O2 MnSOD H2O + O2 CAT H2O + O2 GPx GSH GSSG GR NADP+ TrxS2 Trx(SH)2 Prx TrxR NADPH NADP+
.OH
Fenton reaction
ONOO-
Mitocondria, una fuente de ROS
PGC-1
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PGC-1
Glucose Lipids
Glucose
ATP ATP ROS
ATP
PGC-1
Glucose ATP ROS ATP
PGC-1, a modulator of mitochondrial ROS
80 160 120 40
%
5 mM Gluc 30 mM Gluc
* *
Control Ad Ad- PGC- 1
48 h treatment
ROS
PGC-1 RNA-POL II
TF
Mitochondria
I.Valle et al., CvR, 2005
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PGC-1! +/+ PGC-1! -/-
Isolectin B4 NG2 SMA Isolectin B4 NG2 SMA
PGC-1 +/+ PGC-1-/-
Perdida de recubrimiento pericítico y baja perfusión en ausencia de PGC-1
%
5 10 15 20 25 30 35 2 4 6 8 10 12 14 16 18
Area (%) Area (%) Iso B4 SMA NG2/edge NG2/center
PGC-1a
+/+
PGC-1a
- /-
* * *
PGC-1! +/+ PGC-1! -/-
PGC-1α+/+ PGC-1α-/- PGC-1α-/- PGC-1α+/+
10 20 30 40 2 4 6 8 10 PGC-1! !"#"! PGC-1! !$
#$ !
% ! a.u.
PGC-1! !
"#"!
PGC-1! !$
#$ !
% Mean Intensity Area % !
- N. García-Quintans et al., Angiogénesis, 2016
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PGC-1α+/+ PGC-1α-/- OIR induce la translocación de VE-Cadherin al citosol en ausencia de PGC-1
1E+10 2E+10 3E+10 4E+10 5E+10 6E+10 7E+10 8E+10 9E+10 1E+11
OIR
PGC-1a
+/+
PGC-1a
- /-
Membrane Cytosol
*
- N. García-Quintans et al., Angiogénesis, 2016
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PGC- 1α+/+ PGC- 1α-/- PGC-1α+/+ PGC-1α-/- Torduosidad y hemorragias en ausencia de PGC-1
PGC-1a+/+ PGC-1a-/- PGC-1a+/+ PGC-1a-/- PGC-1a+/+ PGC-1a-/-
Primary plexus
DSD*
PGC-1α-/- PGC-1α+/+
20 40 60 80 0! 5! 10! 15! 20! 25!
PGC-1! !
"#"! PGC-1! ! $ #$ !
PGC-1! !
"#"! PGC-1! ! $ #$ !
Hemorrhage Area Number of Hemorrhages
% ! % !
- N. García-Quintans et al., Angiogénesis, 2016
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Antioxidant treatment improves vascular stability
Area (%) Iso B4 NG2 SMA
PGC-1a
+/+
PGC-1a
- /-
*
Vehicle EUK-189 Vehicle EUK-189 Primary plexus Inner plexus
Primary plexus
DSD* Vehicle EUK-189 Vehicle EUK-189
OIR PGC-1α-/-
Iso B4 NG2
EUK-189 V OIR PGC-1α-/-
- N. García-Quintans et al., Angiogénesis, 2016
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Iso B4 EUK-189 V
El tratamiento con antioxidantes no recupera la polaridad de las células tip
PGC-1α+/+ PGC-1α-/- PGC-1α+/+ Iso B4 PGC-1α-/-
- N. García-Quintans et al., Angiogénesis, 2016
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IPC induces perivascular fibrosis in the absence of PGC-1α
- C. Sánchez-Ramos et al., ARS, 2017
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MEMORY Prevalence of mitochondrial dysfunction in T2D
- The mtDNA
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