Objective: Atherosclerosis, the main pathology underlying cardiovascular diseases is
accelerated in diabetic patients. Genetic mouse models require breeding efforts which
are time-consuming and costly. Our aim was to establish a new nongenetic model of
inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and
allows the detection of phenotypic differences dependent on the metabolic stressor(s).
Methods and Results: Wild-typemice were injected with gain-of-function PCSK9D377Y
(proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles
(AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a
high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis,
two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery)
were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi)
mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis
when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic
plaques of HGHCi HFD animals were larger, showed a less stable phenotype
(measured by the increased necrotic core area, reduced fibrous cap thickness, and
less a-SMA-positive area) and had more inflammation (increased plasma IL-1b level,
aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA)
after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were
confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more
genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia
than in the hyperlipidemia-only group. The HGHCi-associated genes were related to
pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and
extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with
PD, the PD aggravated atherosclerosis to a greater extent in mice and showed
plaque formation after 8 weeks. Hyperlipidemic and hyperglycemicmice fed a PD (HGHCi
PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells)
within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a
directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in
which atherosclerosis is severe by 8 weeks.
Conclusion: We established a nongenetically inducible mouse model allowing
comparative analyses of atherosclerosis in HCi and HGHCi conditions and its
modification by diet, allowing analyses of multiple metabolic hits in mice.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84551 |
| Date | 04 April 2023 |
| Creators | Gaul, Susanne, Shahzad, Khurrum, Medert, Rebekka, Gadi, Ihsan, Mäder, Christina, Schumacher, Dagmar, Wirth, Angela, Ambreen, Saira, Fatima, Sameen, Boeckel, Jes-Niels, Khawaja, Hamzah, Haas, Jan, Brune, Maik, Nawroth, Peter P., Isermann, Berend, Laufs, Ulrich, Freichel, Marc |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2297-055X, 813215 |
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