Abstract
BackgroundPDZK1 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.Principal FindingsHere, 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.ConclusionsThese 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.
Highlights
Hypercholesterolemia is recognized as one of the most important predisposing risk factors for the development of occlusive coronary arterial atherosclerosis and myocardial infarction [1]
These results show that Paigen-diet fed PDZK1/apolipoprotein E (apoE) double KO (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
The Paigen diet-fed PDZK1/apoE dKO mice represent a new murine model of coronary heart disease and suggest that PDZK1 may represent a valuable target for therapeutic intervention
Summary
Hypercholesterolemia is recognized as one of the most important predisposing risk factors for the development of occlusive coronary arterial atherosclerosis and myocardial infarction [1]. 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 [2]). High density lipoprotein (HDL) and its receptor, scavenger receptor class B type I (SR-BI), have been described as atheroprotective [8,9,10,11,12]. They participate in the transport of cholesterol from peripheral tissues (e.g. atheromatous plaques) to the liver and subsequent excretion into the bile, a process called reverse cholesterol transport [13,14,15]. 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
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