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Impaired Arteriolar Dilation in a Mouse Model of Familial Hypercholesterolemia: Impact of Chronic Exercise and Anti‐Cholesterol Therapy
Author(s) -
Stapleton Phoebe A.,
Goodwill Adam G.,
Morrisette Michael R.,
James Milinda E.,
Frisbee Jefferson C.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.593.5
Subject(s) - dilator , medicine , inflammation , simvastatin , endothelial dysfunction , oxidative stress , endocrinology , probucol , dyslipidemia , antioxidant , cholesterol , obesity , chemistry , biochemistry
Hypercholesterolemia is a strong risk factor for negative cardiovascular outcomes and, while mechanistic benefits of ameliorative therapies have not been fully elucidated, it has been clearly demonstrated that evolution of familial hypercholesterolemia (FH) can culminate in profound impairments to microvascular function. To interrogate thus, we hypothesized that FH‐induced increases in oxidant stress and inflammation will impair skeletal muscle resistance arteriolar dilation due to a decreased NO bioavailability. Vascular responses to NO‐dependent stimuli were attenuated with FH, and responses were improved by antioxidant treatment, suggesting oxidant scavenging of NO. Chronic ingestion of ezetimibe/simvastatin did not restore vascular reactivity with FH, but improved inflammation through reductions to TNF‐α, IL‐6, and CRP. Chronic swimming exercise caused minor improvements to vascular dilation, but improved antioxidant protection through increased SOD‐1 and catalase expression. Combination therapy improved dilator reactivity, and lowered inflammation and oxidant stress. Taken together, these observations suggest that genetic dyslipidemia creates a condition wherein endothelial function is compromised, negatively impacting dilator responses. Interventions which can reduce both oxidant stress and chronic inflammation appear to be effective in improving endothelial function.