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Objectives-The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner. Methods and Results-Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (nϭ52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronaryϾthoracic aortaϾ Ͼcarotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronariesϾthoracic aortaeϾcarotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA 2 mRNAs) were only upregulated at 6 months in coronary arteries. Key Words: atherosclerosis Ⅲ diabetes Ⅲ hypercholesterolemia Ⅲ animal models Ⅲ mRNA A therosclerosis is a multi-factorial pathological process resulting from environmental and genetic influences involving multiple vascular territories. Patients with diabetes mellitus (DM) have an increased risk of developing accelerated cardiovascular disease which is potentiated by hypercholesterolemia (HC). 1 Although gene expression of atherosclerotic genes is associated with the presence of atherosclerosis, the sequence of specific gene regulation and the relationship to subsequent development of atherosclerosis is incompletely understood. Also unclear is whether development of atherosclerosis in separate vascular beds is associated with differential gene expression. Conclusions-VariableWe hypothesized that genes relating to vascular cholesterol metabolism, insulin pathways, and inflammatory responses are differentially regulated in a site-specific and time-dependent manner. We tested this hypothesis in the atherosclerotic DM/HC swine model which develops advanced coronary lesions within 6 months. 2 We chose genes that had previously (1) shown differential expression in stable and unstable human atherosclerotic plaques, (2) demonstrated involvement in the atherosclerotic process, and (3) had a pig ortholog. 3 MethodsDiabetes mellitus was induced in male pigs (nϭ52) weighing 25 to 30 kg by 125 mg/kg of intravenous streptozotocin (Sicor Pharmaceuticals). Exogenous insulin was administered to insure that glucose levels did not exceed 350 mg/dL. The animals were fed chow containing 0.5% to 2% cholesterol, 5% to 20% lard, and 1.5% sodium cholate (Animal Specialties) to achieve a cholesterol level of 250 to 1000 mg/dL. Animals were euthanized at 1, 3, 6, or 9 months after induction. The protocol followed institutional guidelines. Histological EvaluationPlease see supplemental methods, available online at http://atvb....

Interstitial nephritis occurs spontaneously in kd/kd mice, but the mechanisms leading to this disease have not been fully elucidated. The earliest manifestation of a phenotype is the appearance of ultrastructural defects in the mitochondria of mice as young as 42 days of age. To examine the influence of the environment on the phenotype, homozygous B6.kd/kd mice were transferred from specific pathogen-free (SPF) conditions to a germfree (GF) environment, and the development of the disease was observed. The GF state resulted in a highly significant reduction in the frequency of tubulointerstitial nephritis. In addition, GF conditions markedly reduced the appearance of the mitochondrial phenotype, with no sign of mitochondrial abnormalities in GF mice of up to 155 days of age. These results suggest that environmental factors are involved in the progression of all known manifestations of this disease phenotype.

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INTRODUCTIONATP turnover in muscle during high-intensity exhaustive exercise and exposure to hypoxia is primarily supported by substrate-level phosphorylation [creatine phosphate (PCr) hydrolysis and glycolysis], which serves to compensate for the metabolic demands that exceed the capacity of mitochondrial oxidative phosphorylation (Hochachka and Somero, 2002). During hypoxia exposure, hypoxia-tolerant animals, such as the common carp, typically suppress ATP turnover because of an inhibition of mitochondrial function; they rely on substrate-level phosphorylation to maintain energy balance (Bickler and Buck, 2007). By contrast, ATP turnover in white muscle during exhaustive exercise can increase by up to 40-fold (Moyes and West, 1995;Richards et al., 2002a), well beyond the capacity of oxidative phosphorylation to supply ATP and therefore PCr hydrolysis and glycolysis are coordinately increased to support a power output that exceeds oxidative capacity. Although the reasons for the activation of substrate-level phosphorylation during exhaustive exercise or exposure to hypoxia differ, the end metabolic profiles are similar, with low muscle [glycogen] and [PCr], and high [lactate] and metabolic [H + ] (Richards et al., 2007;Wang et al., 1994). In spite of these similar metabolic profiles, no study has directly compared recovery metabolism following exhaustive exercise and exposure to hypoxia.During recovery from exhaustive exercise and hypoxia, pathways must be activated to resynthesize PCr and glycogen. The recovery of these metabolites will be linked because of their dependence on mitochondrial ATP production and metabolic H + use. In particular, the rate of PCr and intracellular pH (pH i ) recovery following exercise or hypoxia exposure will be linked through the creatine kinase catalyzed reaction:where mitochondrial ATP serves as the phosphate donor for free creatine accumulated during the metabolic insult. Phosphocreatine hydrolysis will have an alkalinizing effect on the intracellular fluid, whereas PCr synthesis during recovery will have an acidifying effect. As a result, during recovery there is an almost complete recovery of PCr before pH i and lactate begin to return to normoxic resting levels (Richards et al., 2002b;Schulte et al., 1992;van den Thillart et al., 1989;Wang et al., 1994). Creatine kinase is a near-equilibrium reversible enzyme (Lawson and Veech, 1979) ]. In addition, changes in ATP, ADP free and H + play a dominant role in regulating mitochondrial oxidative phosphorylation and glycogensis, and therefore these metabolites functionally link and coordinate metabolism during recovery.Rates of metabolism and ATP production are strongly influenced by temperature in ectothermic animals, thus temperature acclimation may affect rates of metabolic recovery. Temperature acclimation has been shown to result in dramatic changes in muscle properties that allow many ectothermic fish to maintain activity over a wide range of environmental temperatures (Guderley, 2004). This is in part due to an inverse c...

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