Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor
Rationale: Animal models have been used to explore factors that regulate atherosclerosis. More recently, they have been used to study the factors that promote loss of macrophages and reduction in lesion size after lowering of plasma cholesterol levels. However, current animal models of atherosclerosis regression require challenging surgeries, time-consuming breeding strategies, and/or methods that block liver lipoprotein secretion.
Objective: We sought to develop a more direct and time-effective method to create and then reverse hypercholesterolemia as well as atherosclerosis via transient knockdown of the hepatic LDL receptor (LDLR) followed by its rapid restoration.
Methods and Results: We used antisense oligonucleotides directed to LDLR mRNA to create hypercholesterolemia in wild type C57BL/6 mice fed an atherogenic diet. This led to the development of lesions in the aortic root, aortic arch, and brachiocephalic artery. Use of a sense oligonucleotide replicating the targeted sequence region of the LDLR mRNA rapidly reduced circulating cholesterol levels due to recovery of hepatic LDLR expression. This led to a decrease in macrophages within the aortic root plaques and brachiocephalic artery, i.e. regression of inflammatory cell content, after a period of 2-3 weeks.
Conclusions: We have developed an inducible and reversible hepatic LDLR knockdown mouse model of atherosclerosis regression. While cholesterol reduction decreased early en-face lesions in the aortic arches, macrophage area was reduced in both early and late lesions within the aortic sinus after reversal of hypercholesterolemia. Our model circumvents many of the challenges associated with current mouse models of regression. The use of this technology will potentially expedite studies of atherosclerosis and regression without use of mice with genetic defects in lipid metabolism.
- aortic root
- low-density lipoprotein cholesterol
- lipids and lipoprotein metabolism
- murine model
- aortic arch
- Received May 18, 2017.
- Revision received January 4, 2018.
- Accepted January 9, 2018.