Redox-sensitive myocardial remodeling and dysfunction in swine diet-induced experimental hypercholesterolemia.
OBJECTIVE
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.
Zhu
Xiang-Yang
XY
Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN 55905, United States.
Daghini
Elena
E
Rodriguez-Porcel
Martin
M
Chade
Alejandro R
AR
Napoli
Claudio
C
Lerman
Amir
A
Lerman
Lilach O
LO
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005355:Fibrosis; D006937:Hypercholesterolemia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology
D002791:Cholesterol, Dietary; D024042:Collagen Type I; D024061:Collagen Type III; D017931:DNA Primers; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1