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 red...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2010
|
| Online Access: | http://hdl.handle.net/1721.1/54714 https://orcid.org/0000-0003-4541-5181 https://orcid.org/0000-0001-9905-5316 |
| _version_ | 1826211426300067840 |
|---|---|
| author | Krieger, Monty Yesilaltay, Ayce Kocher, Olivier Pal, Rinku Daniels, Kathleen |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Krieger, Monty Yesilaltay, Ayce Kocher, Olivier Pal, Rinku Daniels, Kathleen |
| author_sort | Krieger, Monty |
| collection | MIT |
| description | 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 (~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 Findings: 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. |
| first_indexed | 2024-09-23T15:05:59Z |
| format | Article |
| id | mit-1721.1/54714 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:05:59Z |
| publishDate | 2010 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/547142022-09-29T12:40:31Z Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice Krieger, Monty Yesilaltay, Ayce Kocher, Olivier Pal, Rinku Daniels, Kathleen Massachusetts Institute of Technology. Department of Biology Krieger, Monty Krieger, Monty Yesilaltay, Ayce 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 (~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 Findings: 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. United States. National Institutes of Health (HL-52212, HL66105, HL077780) 2010-05-05T16:05:13Z 2010-05-05T16:05:13Z 2009-12 2009-08 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/54714 Yesilaltay, Ayce et al. “Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice.” PLoS ONE 4.12 (2009): e8103. https://orcid.org/0000-0003-4541-5181 https://orcid.org/0000-0001-9905-5316 en_US http://dx.doi.org/10.1371/journal.pone.0008103 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Krieger, Monty Yesilaltay, Ayce Kocher, Olivier Pal, Rinku Daniels, Kathleen Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice |
| title | Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice |
| title_full | Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice |
| title_fullStr | Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice |
| title_full_unstemmed | Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice |
| title_short | Loss of PDZK1 Causes Coronary Artery Occlusion and Myocardial Infarction in Paigen Diet-Fed Apolipoprotein E Deficient Mice |
| title_sort | loss of pdzk1 causes coronary artery occlusion and myocardial infarction in paigen diet fed apolipoprotein e deficient mice |
| url | http://hdl.handle.net/1721.1/54714 https://orcid.org/0000-0003-4541-5181 https://orcid.org/0000-0001-9905-5316 |
| work_keys_str_mv | AT kriegermonty lossofpdzk1causescoronaryarteryocclusionandmyocardialinfarctioninpaigendietfedapolipoproteinedeficientmice AT yesilaltayayce lossofpdzk1causescoronaryarteryocclusionandmyocardialinfarctioninpaigendietfedapolipoproteinedeficientmice AT kocherolivier lossofpdzk1causescoronaryarteryocclusionandmyocardialinfarctioninpaigendietfedapolipoproteinedeficientmice AT palrinku lossofpdzk1causescoronaryarteryocclusionandmyocardialinfarctioninpaigendietfedapolipoproteinedeficientmice AT danielskathleen lossofpdzk1causescoronaryarteryocclusionandmyocardialinfarctioninpaigendietfedapolipoproteinedeficientmice |