OBJECTIVES: The effects of hypercholesterolemia (HC) on the myocardium and the underlying mechanisms are unclear. We tested the hypothesis that diet-induced HC-induced myocardial fibrosis by regulating the transforming growth factor (TGF)-beta pathway and apoptosis through increased oxidative stress, and that these would be functionally consequential. METHODS: Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet, or HC+antioxidant supplementation. Cardiac function was evaluated by electron beam computed tomography, while fibrogenic mechanisms and apoptosis were evaluated in myocardial tissue. RESULTS: HC-induced myocardial fibrosis was accompanied by increased ratio of interstitial collagen I/III (1.4+/-0.3 versus 0.5+/-0.1 in normal, p<0.05), expression of TGF-beta1 and its downstream smad mediators, as well as myocyte apoptosis. These alterations were also associated with a decrease in diastolic filling rate compared to normal (134.0+/-10.6 ml/s versus 70.3+/-14.3 ml/s, p<0.05), but were attenuated in HC animals chronically supplemented with antioxidants. CONCLUSIONS: Myocardial injury elicited by experimental HC includes redox-sensitive increases in TGF-beta1 expression and apoptosis, which are associated with diastolic dysfunction. These observations underscore a role of increased oxidative stress in modulating myocardial tissue remodeling and dysfunction in vivo in HC.
OBJECTIVES: The effects of hypercholesterolemia (HC) on the myocardium and the underlying mechanisms are unclear. We tested the hypothesis that diet-induced HC-induced myocardial fibrosis by regulating the transforming growth factor (TGF)-beta pathway and apoptosis through increased oxidative stress, and that these would be functionally consequential. METHODS: Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet, or HC+antioxidant supplementation. Cardiac function was evaluated by electron beam computed tomography, while fibrogenic mechanisms and apoptosis were evaluated in myocardial tissue. RESULTS:HC-induced myocardial fibrosis was accompanied by increased ratio of interstitial collagen I/III (1.4+/-0.3 versus 0.5+/-0.1 in normal, p<0.05), expression of TGF-beta1 and its downstream smad mediators, as well as myocyte apoptosis. These alterations were also associated with a decrease in diastolic filling rate compared to normal (134.0+/-10.6 ml/s versus 70.3+/-14.3 ml/s, p<0.05), but were attenuated in HC animals chronically supplemented with antioxidants. CONCLUSIONS:Myocardial injury elicited by experimental HC includes redox-sensitive increases in TGF-beta1 expression and apoptosis, which are associated with diastolic dysfunction. These observations underscore a role of increased oxidative stress in modulating myocardial tissue remodeling and dysfunction in vivo in HC.
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Authors: Louis M Chu; Michael P Robich; Cesario Bianchi; Jun Feng; Yuhong Liu; Shu-Hua Xu; Thomas Burgess; Frank W Sellke Journal: Am J Physiol Heart Circ Physiol Date: 2011-10-28 Impact factor: 4.733
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