Ischemic heart disease remains one of the leading causes of death [1,2]. It is most often caused by occlusive coronary arterial atherosclerosis, which can lead to the development of myocardial infarctions, heart failure, and death. Therapies to prevent myocardial infarctions are of great interest clinically, and mouse models of coronary atherosclerosis allow for the study of disease pathways and additional therapeutic approaches [3]. Many of the commonly used mouse models of atherosclerosis are based on the direct or indirect loss or alteration of the activities of either apolipoprotein E (apoE, including the apoE knockout (KO) [4,5], apoE*3-Leiden and apoE*3-Leiden/CETP tg [6,7], hypomorphic apoE [8]), or the LDL receptor (LDLR, including the LDLR knockout [9] or PCSK9 overexpression [10,11]). However, most of these do not develop robust atherosclerosis in the coronary arteries [[12], [13], [14]], which poses a significant challenge to researchers exploring new therapies and underlying pathways for coronary artery disease (CAD) [15,16]. A number of non-surgical, genetically modified mice fed a high cholesterol or high cholesterol and high fat (Western-type) diet have been shown to exhibit coronary atherosclerosis and myocardial infarction, including i) apoE KO mice crossed with mice with either a macrophage-targeted urokinase-type plasminogen activator transgene (uPA-tg) [17], eNOS KO [18], nNOS KO [19], or the most common dominant Marfan syndrome mutation (Fbn1C1039G+/−) [20] and ii) e/i/nNOS triple KO (tKO) mice [21]. An additional a set of engineered mouse models exhibiting robust and rapid fatal occlusive coronary arterial atherosclerotic disease has been reported. These mice are based on defects in the HDL receptor, Scavenger Receptor, class B, type 1 (SR-B1) [22], or its adaptor protein PDZK1 [23,24] combined with mutations in either the apoE or LDLR genes [4,5,8,9,[25], [26], [27], [28], [29], [30], [31], [32]]. They exhibit rapid onset, occlusive coronary arterial atherosclerosis, myocardial infarctions, heart dysfunction (e.g., reduced ejection fraction), and usually premature death, but often require cumbersome and costly husbandry because of the female infertility and partially penetrant embryonic lethality of SR-B1 KO mice [25,33] or severe pathology arising prior to sexual maturation (e.g., see reference 32). Deletion of the three C-terminal amino acids from SR-B1 (SR-B1ΔCT) interferes with the receptor's binding to the adaptor protein PDZK1 [23,[34], [35], [36]], and SR-B1ΔCT/apoE KO mice develop spontaneous, rapid-onset fatal coronary artery disease [32]. Covey, Trigatti, and colleagues showed that SR-B1/LDLR double knockout (dKO) mice exhibit atherogenic diet-inducible fatal coronary artery disease [28]. As SR-B1ΔCT mice exhibit normal fertility [32], we generated SR-B1ΔCT/LDLR KO mice. Our expectation was that these mice fed a standard chow diet would breed as easily as wild-type mice (normal fertility) and develop coronary artery disease when fed an atherogenic diet, but not when fed a normal, standard, chow diet. As demonstrated here, these expectations have been realized. These mice exhibit rapid-onset, diet-induced, fatal CAD, with decreased cardiac function after initiation of feeding an atherogenic (Paigen) diet [37,38], and then begin to die around three weeks later. We suggest that SR-B1ΔCT/LDLR KO mice will serve as a time-, cost-, and effort-efficient animal model for testing potential therapeutics, some of which might eventually be used to improve patient care.

The current clinical therapies to prevent and treat coronary artery disease-based heart failure rely on the use of lifelong medications or surgical interventions [39,40]. There are limited methods to prevent ischemic damage after myocardial infarction and subsequent heart failure [39]. SR-B1ΔCT/LDLR KO mice should help investigate, characterize, and optimize potential therapeutics [40].

One important therapeutic approach to compensate for atherosclerotic occlusion of coronary arteries is stimulating formation of collateral arteries to bypass the occlusion [41]. We and others have shown that the chemokine Stromal Cell-Derived Factor-1 alpha (SDF-1α, also called CXCL12a) induces arteriogenesis and can attenuate myocardial injury after surgically induced ischemia [[42], [43], [44], [45], [46], [47]]. SDF-1α-induced formation of collateral vessels can provide an alternative source of blood to prevent ischemia, hypoxia, and thus, infarction. Here we have exploited the diet-inducible coronary artery disease in SR-B1ΔCT/LDLR KO mice to explore the potential therapeutic benefit of administering SDF-1α (assessed by measuring cardiac function and the recruitment of endothelial progenitor cells) in the context of ischemia induced by occlusive atherosclerosis.