Transgenic rabbits as models for atherosclerosis research

Abstract

Several characteristics of the rabbit make it an excellent model for the study of lipoprotein metabolism and atherosclerosis. New Zealand White (NZW) rabbits have low plasma total cholesterol concentrations, high cholesteryl ester transfer protein activity, low hepatic lipase (HL) activity, and lack an analogue of human apolipoprotein (apo) A-II, providing a unique system in which to assess the effects of human transgenes on plasma lipoproteins and atherosclerosis susceptibility. Additionally, rabbit models of human lipoprotein disorders, such as the Watanabe Heritable Hyperlipidemic (WHHL) and St. Thomas' Hospital strains, models of familial hypercholesterolemia and familial combined hyperlipidemia, respectively, allow for the assessment of candidate genes for potential use in the treatment of dyslipoproteinemic patients. To date, transgenes for human apo(a), apoA-I, apoB, apoE 2 , apoE 3 , HL, and lecithin:cholesterol acyltransferase (LCAT), as well as for rabbit apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1), have been expressed in NZW rabbits, whereas only those for human apoA-I and LCAT have been introduced into the WHHL background. All of these transgenes have been shown to have significant effects on plasma lipoprotein concentrations. In both NZW and WHHL rabbits, human apoA-I expression was associated with a significant reduction in the extent of aortic atherosclerosis, which was similarly the case for LCAT in rabbits having at least one functional LDL receptor allele. Conversely, expression of apoE 2 in NZW rabbits caused increased susceptibility to atherosclerosis. These studies provide new insights into the mechanisms responsible for the development of atherosclerosis, emphasizing the strength of the rabbit model in cardiovascular disease research. -Brousseau, M. E., and J. M. Hoeg. Transgenic rabbits as models for atherosclerosis research.

Spatially Resolved Transcriptomics for Evaluation of Intracranial Vessels in a Rabbit Model: Proof of Concept

“…There is a robust history of effective research performed using rabbits for investigation of cardiovascular diseases. (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) The current report describes the amenability of rabbits to SRT methods for next generation evaluation of cerebrovascular disorders. To our knowledge, this represents the first report of application of the Visium SRT platform to either rabbits or the intracranial circulation.…”

“…They have a long track record of effective analysis for cardiovascular diseases and subsequent application to cerebrovascular diseases with effective modeling of human disease. (18)(19)(20)(21)(22)(23)(24)(25) Additionally, their size allows for endovascular access to perform minimally invasive techniques, and absence of a rete mirabile allows for catheterization of the intracranial circulation, which cannot be achieved in most other large model animals. (25)(26)(27)(28)(29)(30)(31) As animal models have traditionally been evaluated with histology and immunohistochemical staining, the rapidly progressing fields of genomics and transcriptomics allow for deeper analysis.…”

The COST Manual of Laboratory Animal Care and Use

“…Several characteristics of the rabbit make it an excellent model for the study of lipoprotein • metabolism and atherosclerosis. New Zealand White (NZW) rabbits have low plasma total cholesterol concentrations, high cholesteryl-ester transfer protein activity, low hepatic lipase (HL) activity and lack an analogue of human apolipoprotein apoA-II; this combination provides a unique system for assessing the effects of human transgenes on plasma lipoproteins and susceptibility to atherosclerosis (Brousseau and Hoeg 1999;Zhang et al 2008).…”

Σχέση Δομής - Λειτουργίας Της Απολιποπρωτεΐνης Α-Ι Του Ανθρώπου

“…Οι ίδιοι ερευνητές πρότειναν ότι η αποΑ-ΙΙ μπορεί να αναστέλλει τις αντιαθηρογενετικές ιδιότητες της αποΑ-Ι. Αυτό έχει σαν αποτέλεσμα οι νεοσχηματιζόμενοι εστέρες χοληστερόλης να συσσωρεύονται στην HDL, και να μην μεταφέρονται στην LDL(255). Η υπόθεση αυτή επιβεβαιώθηκε με άλλα πειράματα που έδειξαν ότι η υπερέκφραση της ηπατικής λιπάσης, ή του CETP, σε διαγονιδιακά ποντίκια που υπερεκφράζουν το LCAT, δημιουργεί πιο φυσιολογικά σωματίδια HDL και μειώνει την αθηρωμάτωση που επάγεται από την διατροφή(255,258).…”

“…Αυτό έχει σαν αποτέλεσμα οι νεοσχηματιζόμενοι εστέρες χοληστερόλης να συσσωρεύονται στην HDL, και να μην μεταφέρονται στην LDL(255). Η υπόθεση αυτή επιβεβαιώθηκε με άλλα πειράματα που έδειξαν ότι η υπερέκφραση της ηπατικής λιπάσης, ή του CETP, σε διαγονιδιακά ποντίκια που υπερεκφράζουν το LCAT, δημιουργεί πιο φυσιολογικά σωματίδια HDL και μειώνει την αθηρωμάτωση που επάγεται από την διατροφή(255,258). Τα ποντίκια στα οποία έχει απενεργοποιηθεί το γονίδιο του LCAT Η υπερέκφραση του γονιδίου της ηπατικής λιπάσης σε ποντίκια μειώνει τα επίπεδα της HDL(262), ενώ η απενεργοποίηση του γονιδίου της ηπατικής λιπάσης οδηγεί σε μέτρια αύξηση των επιπέδων της HDL, και την αύξηση 2-3 φορές της ολικής χοληστερόλης(263).…”