Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model, the SR-B1ΔCT/LDLR KO mouse

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-B1 Delta CT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1 alpha), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse. Methods: SR-B1 Delta CT/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-1 alpha 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-1 alpha 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-1 alpha may lead to new therapeutic approaches for ischemic heart disease.