Anne Braun

Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5–6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between ≈3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.

INSECT IMMUNITY. A TRANSGENIC ANALYSIS IN DROSOPHILA DEFINES SEVERAL FUNCTIONAL DOMAINS IN THE DIPTERICIN PROMOTER

Diptericins are antibacterial polypeptides which are strongly induced in the fat body and blood cells of dipteran insects in response to septic injury. The promoter of the single‐copy, intronless diptericin gene of Drosophila contains several nucleotide sequences homologous to mammalian cis‐regulatory motifs involved in the control of acute phase response genes. Extending our previous studies on the expression of the diptericin gene, we now report a quantitative analysis of the contribution of various putative regulatory elements to the bacterial inducibility of this gene, based on the generation of 60 transgenic fly lines carrying different elements fused to a reporter gene. Our data definitively identify two Kappa B‐related motifs in the proximal promoter as the sites conferring inducibility and tissue‐specific expression to the diptericin gene. These motifs alone, however, mediate only minimal levels of expression. Additional proximal regulatory elements are necessary to attain some 20% of the full response and we suspect a role for sequences homologous to mammalian IL6 response elements and interferon‐gamma responsive sites in this up‐regulation. The transgenic experiments also reveal the existence of a distal regulatory element located upstream of ‐0.6 kb which increases the level of expression by a factor of five.

Cellular and physiological roles of SR-BI, a lipoprotein receptor which mediates selective lipid uptake

High-density lipoproteins (HDL) play an important role in protection against atherosclerosis by mediating reverse cholesterol transport - the transport of excess cholesterol from peripheral tissues to the liver for disposal. SR-BI is a cell surface receptor for HDL and other lipoproteins (LDL and VLDL) and mediates the selective uptake of lipoprotein cholesterol by cells. Overexpression or genetic ablation of SR-BI in mice revealed that it plays an important role in HDL metabolism and reverse cholesterol transport and protects against atherosclerosis in mouse models of the disease. If it plays a similar role in humans then it may be an attractive target for therapeutic intervention. We will review some of the recent advances in the understanding of SR-BIs physiological role and cellular function in lipoprotein metabolism.

A short receptor downregulates JAK/STAT signalling to control the Drosophila cellular immune response.

Regulation of JAK/STAT signalling by a short, nonsignalling receptor in Drosophila modulates response to specific immune challenges such as parasitoid infestations.

Myocardial Infarction Following Atherosclerosis in Murine Models

The most widely used mouse models for atherosclerosis are LDL receptor knockout (KO) mice and apolipoprotein E (apoE) KO mice fed standard chow diets or lipid-supplemented diets. Unfortunately, these do not usually exhibit myocardial infarction or other features of human cardiovascular disease such as occlusive coronary artery disease, cardiac dysfunction and/or reduced lifespan. Surgical models of myocardial infarction are successfully used for drug testing analyses during acute ischemia, but do not allow investigation of underlying mechanisms related to atherosclerotic coronary artery disease. Recently, experts in the pharmaceutical industry as well as some at the US Food and Drug Administration have identified inadequate animal models as being one of the major hurdles in drug discovery and development. There is an important need for additional well-characterized, genetically manipulable, small animal models that mimic many features of human coronary heart disease (CHD), which would provide investigators in academia and in the pharmaceutical industry with a better system to unravel the pathophysiology of atherosclerotic CHD and to evaluate pre-clinical drug candidates. Here we will review recently developed mouse models of occlusive CHD, focusing on mice lacking expression of the HDL receptor, SR-BI in the context of reduced expression of apoE.