What is the clinical evidence from this study?

Study design: Other. Population: Atherosclerosis (n=5). Intervention: High-fat and high-fructose (HF/HFru) diet vs. Chow diet. Primary outcome: Lumen reduction due to plaque formation (p=<0.0001).

August 29, 2025iScience3 citationsOpen Access

Single-nucleus profiling of Ossabaw pig atherosclerosis model

Q: What are the key findings of this study?

An atherogenic high-fat and high-fructose diet induced advanced atherosclerotic plaques with calcification and a 42% lumen reduction in Ossabaw pigs, accompanied by transcriptomic phenotypic switches resembling human disease.

OBOlga Bondareva MHMarlene Hausner MKManuela Konert

Key Result

An atherogenic high-fat and high-fructose diet induced advanced atherosclerotic plaques with calcification and a 42% lumen reduction in Ossabaw pigs, accompanied by transcriptomic phenotypic switches resembling human disease.

Structured PICO

Population

5 castrated male Ossabaw pigs aged 16 months were fed an atherogenic or chow diet for 9 months to study the molecular and histological development of atherosclerosis.

Intervention

High-fat and high-fructose diet (HF/HFru) for 9 months

Comparator

Chow diet for 9 months

Outcome

Development of atherosclerosis and molecular characterization via single-nucleus RNA sequencing of aortassurrogate

The Ossabaw pig fed a high-fat/high-fructose diet develops atherosclerosis that closely resembles human disease at the single-nucleus transcriptomic level, establishing it as a valuable preclinical model for cardiovascular research.

Main Result

Absolute Event Rate: 42% vs 3%

p-value: p=<0.0001

Limitations

Small sample size of 5 castrated male pigs.
Conservative data preprocessing may have obscured cross-cell-type transitions.
Genetic differences between pig breeds could affect vascular function and atherosclerosis progression.
Lack of female pigs limits the understanding of sex differences and estrogen's atheroprotective effects.
Incomplete annotation of the swine genome hindered some downstream transcriptomic analysis.
Discrepancy in immune cell representation, with predominantly macrophages in the pig model compared to increased T cell infiltration in human atherosclerosis.

Abstract

Atherosclerosis is a major cause of cardiovascular disease, and accurate preclinical models are essential for developing effective therapies. The Ossabaw pig model has high potential due to its physiological similarity to humans, but its molecular characterization remains limited. To address this, we performed single-nucleus RNA sequencing of over 36,000 nuclei from aortas of Ossabaw pigs fed chow or atherogenic diets. Our analysis revealed activation of brain-derived neurotrophic factor (BDNF), transforming growth factor β (TGF-β), SPP1, and interleukin-2 (IL-2) signaling pathways in atherosclerosis, along with smooth muscle cell transitions to synthetic and pro-osteogenic states, endothelial-to-mesenchymal transition, and TREM2+ immune cell phenotypes. Advanced fibrotic, immune cell-infiltrated plaques with calcification sites paired with molecular changes closely resembled those seen in human atherosclerosis. Together, our findings establish the Ossabaw pig as a valuable translational model and provide high-resolution data to support its use in preclinical cardiovascular research.

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