Effect of Diet Quality and Statin Therapy on Coronary Atherosclerosis and Epicardial Adipose Tissue in the Ossabaw Miniature Pig
Walker, Maura.
2018
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Abstract: Background
and Objective: Current cardiovascular disease risk reduction guidance focuses on overall
dietary patterns, rather than single foods and nutrients. However, due to a lack of
viable animal models few basic research studies have examined the effect of dietary
patterns on coronary artery disease (CAD) development. Additionally, though statin
medications are commonly prescribed ... read morein concurrence with dietary modifications for the
prevention of CAD little data exists on potential diet x statin interactions. Epicardial
adipose tissue (EAT) is the perivascular adipose tissue surrounding the coronary
arteries. EAT inflammation is thought to potentiate the development of CAD and may be
modulated by both diet quality and statin therapy. The objective of this thesis was to
assess the effect of diet quality, statin therapy, and their potential interaction on
coronary atherosclerosis and EAT using the Ossabaw miniature pig model. Methods: To meet
this objective, pigs were fed a Heart Healthy (high in unsaturated fat, unrefined grain,
fruits/vegetables [HHD]) or Western diet (high in saturated fat, cholesterol, refined
grain [WD]) with or without atorvastatin (HHD+S and WD+S). Diets were food-based and
designed to reflect human dietary patterns. Diets were matched for macronutrient
composition and fed in isocaloric amounts. The effect of the respective diets and statin
therapy was assessed by transcriptomic analyses of gene expression in both the left
anterior descending (LAD) coronary artery and the surrounding EAT, and the determination
of EAT fatty acid composition by gas chromatography. Results: The WD, relative to the
HHD, led to the significant differential expression of 142 genes in the LAD coronary
artery. Statin therapy resulted in the significant differential expression of 2 genes
(CHRNB4 and an unknown transcript). Pathway analysis of differential expression
attributable to the WD indicated the up-regulation of 8 pathways related to immune and
inflammatory responses associated with atherosclerosis. EAT of pigs fed the WD, relative
to the HHD, had a 12-fold increase of RSAD2; a gene induced by interferon signaling.
Statin therapy resulted in the differential expression of 17 genes predominately induced
by interferon signaling. A diet x statin interaction was found for 4 genes (IDO1, NKL,
MYL4, and MYL7). Pathway analysis indicated an up-regulation of interferon signaling in
response to the WD, statin therapy, and a potential diet x statin interaction implying
up-regulation in interferon signaling by statin therapy is decreased in EAT of pigs fed
the WD. A signature of all differentially expressed genes in EAT had no significant
association with a histological assessment of atherosclerosis in the LAD. EAT fatty acid
composition largely reflected dietary fat composition. SFAs (total SFAs, capric, lauric,
palmitic and stearic acids) had positive associations with two genes involved in
interferon signaling (IRF7 and IFIT1) and PTGS2. Total n-6 PUFAs, linoleic acid, and n-3
PUFAs (total n-3 PUFAs, α-linolenic, EPA, DPA and DHA) had strong positive
associations with two anti-inflammatory genes (FFAR4 and PPARG), and weak to moderate
positive associations with ALOX5. DHA was negatively associated with IL-1β.
Conclusions: Collectively these findings indicate that poor diet quality, exemplified by
the WD, induces expression of genes implicated in atherosclerosis development in the LAD
coronary artery but did not have a similar effect on EAT gene expression. Statin therapy
and to a lesser extent diet quality, potentially mediated by SFAs, induced changes in
EAT gene expression predominately related to interferon signaling, which was not
significantly associated with the development of coronary atherosclerosis. Results from
this thesis imply that the Ossabaw miniature pig is a valuable model for the study of
dietary patterns and CAD in vivo. However, the modulation of interferon stimulated genes
in EAT may not be a mechanism by which diet quality and statin therapy effect the
development of CAD in the Ossabaw miniature
pig.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Alice Lichtenstein.
Committee: Nirupa Matthan, Susan Fried, and William Johnson.
Keyword: Nutrition.read less - ID:
- v979vf88k
- Component ID:
- tufts:24976
- To Cite:
- TARC Citation Guide EndNote
