Date Published: December 1, 2009
Publisher: Public Library of Science
Author(s): Ayce Yesilaltay, Kathleen Daniels, Rinku Pal, Monty Krieger, Olivier Kocher, Annarosa Leri. http://doi.org/10.1371/journal.pone.0008103
Abstract: 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 (∼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.
Partial Text: Hypercholesterolemia is recognized as one of the most important predisposing risk factors for the development of occlusive coronary arterial atherosclerosis and myocardial infarction . Under typical experimental conditions, neither LDL receptor nor apoE KO mice exhibit robust occlusive coronary artery disease associated with myocardial infarction, heart dysfunction and death during the first six months of life (see for example ). After 8 months (chow diet)  or 5 months (Western diet)  of age, apoE KO mice develop atherosclerotic lesions in the proximal segments of coronary arteries, resulting presumably from the extension of lesions present in the aortic root . Occasional myocardial fibrosis has been observed in 10 month old apoE KO mice . In contrast, there is robust aortic root and aortic atherosclerosis in these mice, and they are commonly used as a model of human atherosclerosis , , .
Animal protocols were reviewed and approved by the respective Animal Care & Use Committees at the Beth Israel Deaconess Medical Center and the Massachusetts Institute of Technology.
We have previously shown that PDZK1 confers protection against aortic root atherosclerosis in apoE KO mice fed an atherogenic, Western-type, high fat/high cholesterol diet for 3 months . Under these conditions, there was no evident occlusive coronary arterial atherosclerosis nor cardiac damage. To explore further the consequences of PDZK1 deficiency in apoE KO mice on atherosclerosis and the heart, we subjected mice to a more severe, cholate-containing atherogenic diet (Paigen diet). Four week-old apoE single and PDZK1/apoE dKO mice were fed a Paigen diet (7.5% cocoa butter, 15.8% fat, 1.25% cholesterol, 0.5% sodium cholate) for three months. At this stage, plasma was obtained and mice were weighed and sacrificed to analyze the extent of aortic root atherosclerosis and cardiac damage.
In this study, we describe a new murine model of diet-induced coronary heart disease, the Paigen-diet-fed PDZK1/apoE dKO mouse. ApoE KO and PDZK1/apoE dKO mice were fed a high fat/high cholesterol diet supplemented with cholate (Paigen diet ) for three months to study the consequences of PDZK1 gene inactivation on lipoprotein metabolism, atherosclerosis and coronary heart disease. Previously, we had shown that PDZK1 deficiency enhances aortic root atherosclerosis in apoE deficient mice on a Western-type high fat/high cholesterol diet, but did not markedly induce occlusive coronary arterial atherosclerosis or myocardial infarction . Consistent with our previous results, we found that PDZK1 is atheroprotective for apoE mice fed the more severe Paigen diet. PDZK1/apoE dKO mice exhibited a 26% increase in the areas of aortic root lesions compared to apoE KO mice. However, unlike the case with Western diet feeding , we found that Paigen diet-fed PDZK1/apoE dKO, but not apoE single KO, mice were characterized by substantial occlusive coronary artery disease and the presence of myocardial infarctions.