Of Cows, Sheep, and

Cardiovascular Disease
HDL and Paraoxonase

Darrell Rubin, MD PhD

Department of Internal Medicine
UH Case Medical Center
Lenz et al Toxicology 233: 31, 2007 Photos from the BBC
 Overview

- Review the relationship between HDL and CVD

- Discuss the structure and function of paraoxonase

- Discuss the relationship between paraoxonase and CVD

- Discuss interventions that affect paraoxonase activity

Reverse Cholesterol Transport

MPO

lipoxygenase

Adapted from Movva et al Clin Chem 54(5): 788-800, 2008

HDL and Risk of CVD

Castelli et al JAMA 256(20): 2835-38, 1986

HDL Properties

Adapted from Movva et al Clin Chem 54(5): 788-800, 2008

HDL Binding Partners

Vaisar et al JCI 117(3): 746, 2007

 Overview

- Review the relationship between HDL and CVD

- Discuss the structure and function of paraoxonase

- Discuss the relationship between paraoxonase and CVD

- Discuss interventions that affect paraoxonase activity

PON structure and function

Li et al J Mol Med 81: 766-779, 2003

James et al. Free Rad Biol & Med 37(12): 1986, 2004
PON expression

Ng et al Free Rad Biol Med 38: 153-163, 2005

 PON substrates

Phenyl acetate Paraoxon

Arylesterase Paraoxonase Aliphatic Lactones

Billecke et al Drug Metab and Dispo 28(11): 1335, 2000

 PON

What is PON?
- Gene family
- polymorphisms
- substrates

Costa et al Biochem Pharm 69: 541-550, 2005

 Overview

- Review the relationship between HDL and CVD

- Discuss the structure and function of paraoxonase

- Discuss the relationship between paraoxonase and CVD

- Discuss interventions that affect paraoxonase activity

 PON and CVD

Shih et al. Nature 394: 284, 1998 Tward et al Circulation 106:484-490, 2002
PON and CVD

McElveen Clin Chem 32(4): 671-3, 1986

Prospective cohort study
Men 49 65 years of age
Recruitment 1984 1988
15 year follow up

Mackness et al Circulation 107: 2775-2779, 2003

Graner et al JACC 47(12): 2429, 2006
Phenyl acetate
Arylesterase
Bhattacharyya et al Jama 299(11): 1265, 2008


Bhattacharyya et al Jama 299(11): 1265, 2008

 Compare and Contrast
Caerphilly Medium Men -Fasting sample
Prospective 49 65 years -No arylesterase
Inclusive 15 year f/u activity

CCF Medium 65% men -Fasting unknown

Selected group 55 - 75 years -Sample antioxidant
3-4 year f/u

PRIME Large Men -Fasting sample

Prospective 50-59 years -No arylesterase
Case-control 5 year f/u activity

Prospect-Epic Large postmenopausal women - Gender difference

Prospective 49-70 years - Nonfasting sample
Case-control 4 8 years f/u - Excluded preexisting
CHD
 Overview

- Review the relationship between HDL and CVD

- Discuss the structure and function of paraoxonase

- Discuss the relationship between paraoxonase and CVD

- Discuss interventions that affect paraoxonase activity

Costa et al Biochem Pharm 69: 541-550, 2005
 Summary

- HDL has many associated proteins and functions which

seem to be important in the development of atherosclerosis.

- PON function has been associated with protection against

atherosclerosis.

- PON function can be modified.