Joscha Mulorz1, Joshua Michael Spin2, Hans Christian Beck3, My Linh Tha Thi4, Markus Udo Wagenhäuser5, Lars Melholt Rasmussen6, Jes Sanddal Lindholt7, Philip Shih Chung Tsao2, Lasse Bach Steffensen8. 1. VA Palo Alto Health Care System, Palo Alto, CA, United States; Stanford University, Department of Cardiovascular Medicine, Stanford, CA, United States; Department of Vascular and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: joscha.mulorz@med.uni-duesseldorf.de. 2. VA Palo Alto Health Care System, Palo Alto, CA, United States; Stanford University, Department of Cardiovascular Medicine, Stanford, CA, United States. 3. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. 4. Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark. 5. Department of Vascular and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. 6. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark. 7. Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark; Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark. 8. Stanford University, Department of Cardiovascular Medicine, Stanford, CA, United States; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark; Unit of Cardiovascular and Renal Research, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Abstract
BACKGROUND AND AIMS: Hyperlipidemia is a suggested risk factor for abdominal aortic aneurysm (AAA). However, whether hyperlipidemia is causally involved in AAA progression remains elusive. Here, we tested the hypothesis that hyperlipidemia aggravates AAA formation in the widely used porcine pancreatic elastase (PPE) model of AAA in mice with varying levels of plasma lipids. METHODS: Prior to PPE-surgery, 8-week-old male C57BL/6J mice (n = 32) received 1·1011 viral genomes of rAAV8-D377Y-mPcsk9 or control rAAV8 via the tail vein. Mice were fed either western type diet or regular chow. At baseline and during the 28 days following PPE-surgery, mice underwent weekly ultrasonic assessment of AAA progression. Experiments were repeated using Apolipoprotein E knockout (ApoE-/-) mice (n = 7) and wildtype C57BL/6J mice (n = 5). RESULTS: At sacrifice, maximal intergroup plasma cholesterol and non-HDL/HDL ratio differences were >5-fold and >20-fold, respectively. AAA diameters expanded to 150% of baseline, but no intergroup differences were detected. This was verified in an independent experiment comparing 8-week-old male ApoE-/- mice with wildtype mice. Histological evaluation of experimental AAA lesions revealed accumulated lipid in neointimal and medial layers, and analysis of human AAA lesions (n = 5) obtained from open repair showed medial lipid deposition. CONCLUSIONS: In summary, we find that lipid deposition in the aortic wall is a feature of PPE-induced AAA in mice as well as human AAA lesions. Despite, our data do not support the hypothesis that hyperlipidemia contributes to AAA progression.
BACKGROUND AND AIMS: Hyperlipidemia is a suggested risk factor for abdominal aortic aneurysm (AAA). However, whether hyperlipidemia is causally involved in AAA progression remains elusive. Here, we tested the hypothesis that hyperlipidemia aggravates AAA formation in the widely used porcine pancreatic elastase (PPE) model of AAA in mice with varying levels of plasma lipids. METHODS: Prior to PPE-surgery, 8-week-old male C57BL/6J mice (n = 32) received 1·1011 viral genomes of rAAV8-D377Y-mPcsk9 or control rAAV8 via the tail vein. Mice were fed either western type diet or regular chow. At baseline and during the 28 days following PPE-surgery, mice underwent weekly ultrasonic assessment of AAA progression. Experiments were repeated using Apolipoprotein E knockout (ApoE-/-) mice (n = 7) and wildtype C57BL/6J mice (n = 5). RESULTS: At sacrifice, maximal intergroup plasma cholesterol and non-HDL/HDL ratio differences were >5-fold and >20-fold, respectively. AAA diameters expanded to 150% of baseline, but no intergroup differences were detected. This was verified in an independent experiment comparing 8-week-old male ApoE-/- mice with wildtype mice. Histological evaluation of experimental AAA lesions revealed accumulated lipid in neointimal and medial layers, and analysis of human AAA lesions (n = 5) obtained from open repair showed medial lipid deposition. CONCLUSIONS: In summary, we find that lipid deposition in the aortic wall is a feature of PPE-induced AAA in mice as well as human AAA lesions. Despite, our data do not support the hypothesis that hyperlipidemia contributes to AAA progression.
Authors: Joscha Mulorz; Mahdis Shayan; Caroline Hu; Cynthia Alcazar; Alex H P Chan; Mason Briggs; Yan Wen; Ankita P Walvekar; Anand K Ramasubramanian; Joshua M Spin; Bertha Chen; Philip S Tsao; Ngan F Huang Journal: Biomater Sci Date: 2021-10-12 Impact factor: 7.590
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Authors: L B Steffensen; J Stubbe; J S Lindholt; H C Beck; M Overgaard; M Bloksgaard; F Genovese; S Holm Nielsen; M L T Tha; S K Bang-Moeller; M K T Hong Lin; J H Larsen; D R Hansen; G T Jones; M J Bown; M A Karsdal; L M Rasmussen Journal: Sci Rep Date: 2021-06-18 Impact factor: 4.379
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