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Cardiovascular Changes in Diabetes

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Cardiovascular Changes in Diabetes Wang Hui-ping Diabetes One of the most common metabolic diseases of our times Specific cardiovascular alterations are often ... – PowerPoint PPT presentation

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Title: Cardiovascular Changes in Diabetes


1
  • Cardiovascular Changes in Diabetes

Wang Hui-ping
2
Diabetes
  • One of the most common metabolic diseases of our
    times
  • Specific cardiovascular alterations are often
    associated with the progression of this disease.
  • A major risk factor leading to increased
    cardiovascular mortality and morbidity

3
The experimental diabetic-rat model
  • Streptozotocin(????)-induced diabetes
  • Male SD rat (175-220g)
  • Intravenous tailvein injection, ip
  • STZ 50-65mg/kg in citrate buffer 0.1mol/L, pH
    4.5
  • Blood glucose measurement glucometer(Upjohn)
  • 1,4 (early), 6, 8, 10, 16(chronic)wk

4
The experimental diabetic-rat model
  • Alloxan(????)-induced diabetes
  • Rat (190g-220g)
  • Intravenous tailvein injection
  • Alloxan 200mg/kg (????)
  • Blood glucose measurement ?????
  • ?(serum)??13.9mmol/L

5
The experimental diabetic-rat model
  • The high glucose incubation model in vitro
  • Normal glucose levels ?5-11mmol/L
  • Diabetic glucose levels gt30mmol/L

6
The experimental diabetic-rat model
  • High glucose-treated myocytes
  • Incubating neonatal rat cardiomyocytes
  • Isolated Ventricular myocytes from adult rats
    were cultured for 24 h with either normal (5.5
    mM) or high (25.5 mM) glucose

7
Histopathology
  • typical diabetic alterations
  • ?Collagen content, vacuolation, lipid drops
  • ?Cardiomyocyte diameter
  • Alteration in myofilaments and Z-lines of
    myofibers
  • Myofibrillary degeneration
  • ? Volume fraction of myofibrils, SR and t-tubules
  • ? Mitochondrial size and volume fraction

8
Histopathology
  • Oxidative damage (? ROS formation)
  • Apoptosis
  • Hyperglycemia?local renin-angiotensin system()
    ?Ang II? ?() endogenous cell death pathway

9
Diabetes-induced cardiac mechanical
dysfunctions--organ level
  • Depressed contraction
  • Slow relaxation
  • Increased Chamber volume
  • HR?
  • ? Density of myocardial ?-AR
  • Supersensitivity to negative chronotropic effects

10
Diabetes-induced cardiac mechanical
dysfunctions--cell level
  • ?PS
  • ??dL/dt
  • Prolonged duration of shortening
  • Prolonged duration of relengthening

11
Altered electrophysiological characteristics
  • Prolongation of APD
  • ?Ca(2)-independent transient outward K()
    current (I(t))
  • ? Steady-state outward K() current (I(ss))
  • Slowed inactivation of the L-type Ca(2) current
    (I(CaL))

12
Altered electrophysiological characteristics
  • A small depolarization in the resting membrane
    potential
  • ? Electrogenic Na()-K() pump current

13
Diabetes-induced intracellular Ca2 transient
changes
  • Prolonged intracellular Ca2 transient
  • ? Resting intracellular Ca2 levels
  • ? Ca2 -induced Ca2 release

14
Impaired Ca2 homeostasis
  • Reduced Ca2 -induced Ca2 release
  • ?Membrane Ca2 channel conduction
  • ?SR Ca2 load
  • Slowed intracellular Ca2 removal
  • ? SR Ca2-ATPase activity
  • Impaired Na /Ca2 exchanger

15
Mechanisms
  • Depressed myofilament Ca2 sensitivity
  • Alterations in Ca2 -calmodulin-dependent protein
    kinase
  • Alterations in myosin isozyme switch (V1?V3)
  • ? SERCA2a protein level
  • ? SR Ca2 content(rapid-cooling contracture
    (RCC))
  • ? Ryanodine binding sites

16
Mechanisms
  • Metabolic derangements
  • (-) Mitochondrial respiatory function and
    pyruvate dehydrogenase

17
Biochemical parameters altered by diabetes
  • ? SOD activity
  • ? Creatine kinase (CK) activity
  • i-NOS was not different

18
diabetic heart and I/R
  • Cardiomyocytes less prone to dysfunctions
    resulting from ischemia and reperfusion
  • Decreased incidence of mitochondrial permeability
    transition (MPT) P-associated features

19
Vascular dysfunction in diabetes
  • 74 die of vascular complications
  • Impaired endothelium-dependent relaxation(EDR)
  • Possible mechanisms
  • High destruction of NO by O2-derived free
    radicals
  • Release of endothelium-derived vasoconstrictors
  • Low formation of NO
  • Low availability and/or high destruction of NO
  • Enhanced ROS .O2-, H2O2?.OH

20
Vascular dysfunction in diabetes
  • Increased responses to PE, NE
  • PE, NE?()?-AR ?()PLC ?IP3, DG? ?Ca2 relaese ?
    (from SR)
  • () voltage-dependent Ca2 channel

21
Vascular dysfunction in diabetes
  • Diabetic aorta
  • Impaired Ang II-induced cytosolic calcium
    Ca(2) signal
  • Reduced type I IP3R expression

22
Diabetes and IL-2
  • Proinflammatory cytokines TNFalpha, INFgamma,
    IL-1alpha and IL-2 may play important roles alone
    or in combination in the pathogenesis of type 1
    diabetes mellitus--J Pediatr Endocrinol Metab.
    2003 Feb16(2)203-10

23
  • There was a significant correlation between serum
    IL-2 levels and insulin sensitivity--J Int Med
    Res. 2002 Jul-Aug30(4)386-90

24
  • significantly in the pancreas of NOD mice--J
    Autoimmun. 2001 Dec17(4)281-7
  • Interleukin 2 (IL-2)--a Th1 lymphocyte-derived
    cytokine is at present considered to play an
    important role in the etiopathogenesis of
    insulin-dependent diabetes mellitus. --Arch
    Immunol Ther Exp (Warsz). 199947(1)45-9

25
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