Yvonne Baumer1, Sara McCurdy1, Xueting Jin2, Tina M Weatherby3, Amit K Dey4, Nehal N Mehta4, Jonathan K Yap1, Howard S Kruth2, William A Boisvert5. 1. Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, Honolulu, HI, 96813, USA. 2. Section of Experimental Atherosclerosis, National Heart, Lung and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA. 3. Pacific Biosciences Research Center, Biological Electron Microscope Facility, University of Hawaii, 2538 The Mall, Snyder Hall, Honolulu, HI, 96822, USA. 4. Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA. 5. Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, Honolulu, HI, 96813, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia. Electronic address: wab@hawaii.edu.
Abstract
BACKGOUND AND AIMS: The low-density lipoprotein receptor-deficient (Ldlr-/-) mouse has been utilized by cardiovascular researchers for more than two decades to study atherosclerosis. However, there has not yet been a systematic effort to document the ultrastructural changes that accompany the progression of atherosclerotic plaque in this model. METHODS: Employing several different staining and microscopic techniques, including immunohistochemistry, as well as electron and polarized microscopy, we analyzed atherosclerotic lesion development in Ldlr-/- mice fed an atherogenic diet over time. RESULTS: Lipid-like deposits occurred in the subendothelial space after only one week of atherogenic diet. At two weeks, cholesterol crystals (CC) formed and increased thereafter. Lipid, CC, vascular smooth muscles cells, and collagen progressively increased over time, while after 4 weeks, relative macrophage content decreased. Accelerated accumulation of plate- and needle-shaped CC accompanied plaque core necrosis. Lastly, CC were surrounded by cholesterol microdomains, which co-localized with CC through all stages of atherosclerosis, indicating that the cholesterol microdomains may be a source of CC. CONCLUSIONS: Here, we have documented, for the first time in a comprehensive way, atherosclerotic plaque morphology and composition from early to advanced stages in the Ldlr-/- mouse, one of the most commonly used animal models utilized in atherosclerosis research.
BACKGOUND AND AIMS: The low-density lipoprotein receptor-deficient (Ldlr-/-) mouse has been utilized by cardiovascular researchers for more than two decades to study atherosclerosis. However, there has not yet been a systematic effort to document the ultrastructural changes that accompany the progression of atherosclerotic plaque in this model. METHODS: Employing several different staining and microscopic techniques, including immunohistochemistry, as well as electron and polarized microscopy, we analyzed atherosclerotic lesion development in Ldlr-/- mice fed an atherogenic diet over time. RESULTS:Lipid-like deposits occurred in the subendothelial space after only one week of atherogenic diet. At two weeks, cholesterol crystals (CC) formed and increased thereafter. Lipid, CC, vascular smooth muscles cells, and collagen progressively increased over time, while after 4 weeks, relative macrophage content decreased. Accelerated accumulation of plate- and needle-shaped CC accompanied plaque core necrosis. Lastly, CC were surrounded by cholesterol microdomains, which co-localized with CC through all stages of atherosclerosis, indicating that the cholesterol microdomains may be a source of CC. CONCLUSIONS: Here, we have documented, for the first time in a comprehensive way, atherosclerotic plaque morphology and composition from early to advanced stages in the Ldlr-/- mouse, one of the most commonly used animal models utilized in atherosclerosis research.
Authors: Daniel S Ong; Joshua J Anzinger; Francisco J Leyva; Noa Rubin; Lia Addadi; Howard S Kruth Journal: J Lipid Res Date: 2010-04-26 Impact factor: 5.922
Authors: Yvonne Baumer; Sara McCurdy; Martin Alcala; Nehal Mehta; Bog-Hieu Lee; Mark H Ginsberg; William A Boisvert Journal: Atherosclerosis Date: 2016-11-16 Impact factor: 5.162
Authors: M Accad; S J Smith; D L Newland; D A Sanan; L E King; M F Linton; S Fazio; R V Farese Journal: J Clin Invest Date: 2000-03 Impact factor: 14.808
Authors: Yvonne Baumer; Amit K Dey; Cristhian A Gutierrez-Huerta; Noor O Khalil; Yusuke Sekine; Gregory E Sanda; Jie Zhuang; Ankit Saxena; Erin Stempinski; Youssef A Elnabawi; Pradeep K Dagur; Qimin Ng; Heather L Teague; Andrew Keel; Justin A Rodante; William A Boisvert; Lam C Tsoi; Johann E Gudjonsson; Christopher K E Bleck; Marcus Y Chen; David A Bluemke; Joel M Gelfand; Daniella M Schwartz; Howard S Kruth; Tiffany M Powell-Wiley; Martin P Playford; Nehal N Mehta Journal: EBioMedicine Date: 2020-07-06 Impact factor: 8.143