Thesis (M. Med. Sc.)--University of Queensland, 2003. / Includes bibliographical references.

Atherosclerosis is the major cause of cardiovascular diseases, which constitute the top ten leading causes of death worldwide. Atherosclerotic plaque development initiates from the inflamed endothelium under an atherogenic environment – chronic low grade inflammation, hypercholesterolemia, endotoxemia, etc. The principal cause of such inflammation has yet to be defined – with growing evidence that microbial stimulants like lipopolysaccharide (LPS) and peptidoglycan (PGN), which can activate toll-like receptors (TLRs) and nuclear factor-kappaB (NFκB) signaling might be the plausible origins. The gastrointestinal tract is suggested to be the major site for absorption and translocation of such stimulants, where gut microbiota have been associated with systemic inflammation and is essential in generating atherogenic substances. Since probiotics have the potential to induce systemic anti-inflammatory effects and fortify gut barrier to reduce bacterial translocation, evaluation of whether probiotics can help reduce atherogenesis was done by feeding the disease model, ApoE-/- mice with high fat diet alone, with telmisartan (1 or 5 mg/kg/day, positive controls) or with probiotics VSL#3 (2.8 x 1011 CFU/day) and/or Lactobacillus rhamnosus strain GG (LGG) (1x108 CFU/day), or the combination of which for 12 weeks. All treatments reduced lesion size significantly; with some treatments reduced plasma endotoxin, cholesterol and various proinflammatory biomarkers. The gut microbiota assessed with PCR-amplified 16S rRNA gene sequences using 454 pyrosequencing and thereafter correlation studies revealed that at least 20 bacterial families that were significantly altered by high fat diet in apolipoprotein E knockout (ApoE-/-)mice correlated with atherosclerotic plaque size and related biomarkers including cholesterol, adipocyte fatty acidbinding protein (A-FABP), etc. Probiotics showed potential in improving atherogenic environment by immunomodulation and induction or inhibition of growth of bacteria correlated with the atherosclerotic plaque and biomarkers. The atherosclerotic condition was also improved by telmisartan, which correlated with the altered gut microbiota. The newly identified atherosclerosis-related gut bacteria will require further exploration into their properties and mechanisms, which will eventually lead to the potential of developing probiotics for the treatment or prevention of atherosclerosis, and thus may be used as an affordable and non-invasive alternative that brings health benefits worldwide. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Dietary flaxseed intake has exhibited both cardioprotective and anti-atherogenic properties. Regardless, it remains unclear whether these beneficial effects extent to the regression of atherosclerotic plaques or the resolution of cholesterol-induced vascular contractile dysfunction. In the present study, we intended to determine whether dietary flaxseed has the capacity to ameliorate vascular function abnormalities and induce atherosclerotic plaque regression. As results from previous studies using a nutritional intervention to induce atherosclerotic regression may have been confounded by premature initiation of the intervention, an appropriate feeding regimen was developed to adequately evaluate flaxseeds’ effects on atherosclerotic plaque regression. New Zealand white rabbits were utilized in two studies. To establish clear evidence of plaque growth stabilization, animals received 4 weeks of a 1% cholesterol-supplemented diet. An initial subset of animals was immediately examined. The remaining animals were fed regular rabbit chow and examined at intervals up to 28 weeks. To ascertain flaxseeds’ effects on atherosclerotic plaque regression and vascular contractile function, animals were randomly assigned to a control group fed a regular diet for 12 weeks (Group I) or an experimental group fed a 1% cholesterol-supplemented diet for 4 weeks followed by a regular diet for 8 weeks (Group II). The control and a subset of experimental animals were examined immediately afterwards. The remaining experimental animals were given an additional 8 or 14 weeks of either a regular diet (Group III and V, respectively) or a 10% flaxseed-supplemented diet (Group IV and VI, respectively) and were examined afterwards. Cholesterol feeding followed by 8 weeks of withdrawal from cholesterol not only resulted in the development and stabilization of atherosclerotic plaques but also impaired the maximum contraction caused by norepinephrine and the relaxation response to acetylcholine. An additional 14 weeks of regular diet reduced the amount of plaques on the aorta while flax-supplementation resulted in a further reduction in plaques. Nevertheless, both treatments were unable to achieve statistical significance. Flax- supplemented and regular diets improved vessel relaxation and contraction; however, negligible changes in the relaxation response induced by sodium nitroprusside were observed. Dietary flaxseed may accelerate the regression of atherosclerotic plaques. Moreover, the known beneficial effects of flaxseed do not extend to restoration of vascular function.

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