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Published on: June 3, 2018
Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model,
Danielle M Mullis1, Amanda Padilla-Lopez1, Hanjay Wang1
1Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA.
Insights
A novel mouse model for coronary artery disease allows rapid testing of therapies. Stromal Cell-Derived Factor-1 alpha (SDF-1α) treatment improved cardiac function and survival in mice with diet-induced heart disease.
Area of Science:
- Cardiovascular Biology
- Animal Models of Disease
- Regenerative Medicine
Background:
- Limited pharmacologic options exist for coronary artery disease (CAD).
- Existing rodent models for occlusive coronary atherosclerosis and myocardial infarction are insufficient for rapid therapeutic testing.
- A novel HDL receptor (SR-B1)-based mouse model, SR-B1ΔCT/LDLR KO, is characterized for diet-inducible, fatal coronary atherosclerosis.
Purpose of the Study:
- To characterize a new SR-B1ΔCT/LDLR KO mouse model for studying coronary atherosclerosis.
- To evaluate the therapeutic potential of intramyocardial Stromal Cell-Derived Factor-1 alpha (SDF-1α) injection in this model.
Main Methods:
- SR-B1ΔCT/LDLR KO mice were fed either an atherogenic Paigen diet or a standard chow diet.
- Mice received intramyocardial injections of SDF-1α or phosphate-buffered saline (PBS) after two weeks on the diet.
- Cardiac function, histology, and survival were assessed to determine the effects of diet and treatment.
Main Results:
- Mice on the Paigen diet exhibited significant mortality, cardiomegaly, myocardial infarction, and occlusive coronary artery disease.
- Intramyocardial PBS injection led to a significant decrease in ejection fraction (EF) in surviving mice.
- SDF-1α treatment significantly improved cardiac function (increased EF) and survival rates in mice on the Paigen diet.
Conclusions:
- The SR-B1ΔCT/LDLR KO mouse serves as a valuable model for diet-induced coronary atherosclerosis.
- SDF-1α demonstrates therapeutic promise for ischemic heart disease by improving cardiac function and survival.
- This model and treatment strategy may facilitate the development of new therapies for CAD.
Background And Aims:
There are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse.
Methods:
SR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later.
Results:
When six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease. For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t-test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t-test, n = 8, p = 0.003).
Conclusions:
This new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease.
