CD38 and Ceramide-Enriched Membrane Platforms in Bovine Coronary - - PowerPoint PPT Presentation

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CD38 and Ceramide-Enriched Membrane Platforms in Bovine Coronary - - PowerPoint PPT Presentation

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CD38 and Ceramide-Enriched Membrane Platforms in Bovine Coronary Myocytes July 31, 2008 Matt Childrey Department of Pharmacology & Toxicology Medical College of Virginia Virginia Commonwealth University Richmond, Virginia Summer Program

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SLIDE 1

CD38 and Ceramide-Enriched Membrane Platforms in Bovine Coronary Myocytes

July 31, 2008 Matt Childrey Department of Pharmacology & Toxicology Medical College of Virginia Virginia Commonwealth University Richmond, Virginia Summer Program for Undergraduate Research 2008

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SLIDE 2

Background

  • Ceramide-enriched

microdomains ASM

  • Oxotremorine
  • CD38
  • 45 kDa

sphingomyelin ceramide de novo

lipid rafts

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SLIDE 3

Hypothesis

  • Lipid raft membrane microdomains are

involved in oxotremorine-induced CD38 activation in bovine coronary myocytes.

CD38

  • xotremorine

Lipid raft platform

cADPR hydrolysis Calcium release vasoconstriction

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SLIDE 4

Methods

  • DMT Myograph: tension recording studies of fresh

bovine myocardial vasculature

  • Vasoconstrictor: Oxotremorine (20 uM, 40 uM, 60 uM,

80 uM)

  • Drugs: Methyl-ß-cyclodextrin (1mM), desipramine (0.1

mM), filipin (1µg/mL), nicotinamide ( 6mM), treated for 15 minutes

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SLIDE 5

Results

  • Fig. 1. Effect of LR inhibitors on oxotremorine-induced

constriction

Oxotremorine-induced Contraction

  • xotremorine

0 uM 20 uM 40 uM 60 uM 80 uM

% relative contraction

  • 200

200 400 600 800 1000 control (n=29) mcd (n=29) desipramine (n=13) filipin (n=16) nicotinamide (n=22)

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SLIDE 6

Results

Methyl-ß-cyclodextrin vs. Control

Oxotremorine-induced Contraction (n=29)

  • xotremorine

0 uM 20 uM 40 uM 60 uM 80 uM

% relative contraction

100 200 300 400 500 600 700 control mcd

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SLIDE 7

Results

Desipramine vs. Control

Oxotremorine-induced Contraction

  • xotremorine

0 uM 20 uM 40 uM 60 uM 80 uM

% relative contraction

  • 100

100 200 300 400 500 control (n=29) desipramine (n=13)

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SLIDE 8

Results

Filipin vs. Control

Oxotremorine-induced Contraction

  • xotremorine

0 uM 20 uM 40 uM 60 uM 80 uM

% relative contraction

100 200 300 400 500 control (n=29) filipin (n=16)

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SLIDE 9

Results

Nicotinamide vs. Control

0 uM 20 uM 40 uM 60 uM 80 uM 200 400 600 800 1000 control (n=29) nicotinamide (n=22)

Oxotremorine-induced Contraction

  • xotremorine

% relative contraction

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SLIDE 10

Results

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SLIDE 11

Discussion

  • CD38 as receptor and enzyme
  • ASM inhibition
  • Role of ceramide in CD38 activation?
  • Raft aggregation and oxotremorine

stimulation

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SLIDE 12

Questions and Future Directions

  • Inhibitor concentrations
  • Oxotremorine dosage levels
  • Myograph-specific conditions?
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SLIDE 13

Acknowledgements

  • Dr.Li and Dr.Zou
  • special thanks for making

this summer possible

  • VCU Pharmacology & Toxicology