Loss of PDZK1 causes coronary artery occlusion and myocardial infarction in Paigen diet-fed apolipoprotein E deficient mice.
BACKGROUND
PDZK1 is a four PDZ-domain containing protein that binds to the carboxy terminus of the HDL receptor, scavenger receptor class B type I (SR-BI), and regulates its expression, localization and function in a tissue-specific manner. PDZK1 knockout (KO) mice are characterized by a marked reduction of SR-BI protein expression ( approximately 95%) in the liver (lesser or no reduction in other organs) with a concomitant 1.7 fold increase in plasma cholesterol. PDZK1 has been shown to be atheroprotective using the high fat/high cholesterol ('Western') diet-fed murine apolipoprotein E (apoE) KO model of atherosclerosis, presumably because of its role in promoting reverse cholesterol transport via SR-BI.


RESULTS
Here, we have examined the effects of PDZK1 deficiency in apoE KO mice fed with the atherogenic 'Paigen' diet for three months. Relative to apoE KO, PDZK1/apoE double KO (dKO) mice showed increased plasma lipids (33% increase in total cholesterol; 49 % increase in unesterified cholesterol; and 36% increase in phospholipids) and a 26% increase in aortic root lesions. Compared to apoE KO, dKO mice exhibited substantial occlusive coronary artery disease: 375% increase in severe occlusions. Myocardial infarctions, not observed in apoE KO mice (although occasional minimal fibrosis was noted), were seen in 7 of 8 dKO mice, resulting in 12 times greater area of fibrosis in dKO cardiac muscle.


CONCLUSIONS
These results show that Paigen-diet fed PDZK1/apoE dKO mice represent a new animal model useful for studying coronary heart disease and suggest that PDZK1 may represent a valuable target for therapeutic intervention.
Yesilaltay
Ayce
A
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Daniels
Kathleen
K
Pal
Rinku
R
Krieger
Monty
M
Kocher
Olivier
O
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D054059:Coronary Occlusion / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000473:pathology
D001057:Apolipoproteins E; D018955:CD36 Antigens; D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; D008565:Membrane Proteins; C514896:PDZK1 protein, mouse; C030104:lipoprotein cholesterol; D002784:Cholesterol