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Atorvastatin Increases Myocardial Indices of Oxidative Stress in a Porcine Model of Hypercholesterolemia and Chronic Ischemia
Neel R. Sodha, Munir Boodhwani, Shu-Hua Xu, Basel Ramlawi, Shigetoshi Mieno, Richard T. Clements, Frank W. Sellke
Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA
Objective: Atorvastatin has previously been shown to reduce the endogenous angiogenic response to chronic myocardial ischemia in a porcine model. One possible mechanism for this effect is reduced bioavailability of nitric oxide, a key mediator of angiogenesis, secondary to increased oxygen free radicals. We sought to determine if atorvastatin modulates oxidative stress in myocardial tissue.
Design: Controlled Animal Experimental Study
Setting: Tertiary Care Academic Hospital
Animals: Hypercholesterolemic Yucatan Miniswine
Intervention: Dietary induction of hypercholesterolemia was performed over 13 weeks, with treated animals receiving oral atorvastatin 3mg/kg/day. An ameroid constrictor ring was surgically placed around the proximal left circumflex coronary artery via minithoracotomy at 13 weeks to induce gradual onset chronic ischemia. 7 weeks after ameroid placement, hearts were harvested.
Main Outcome Measures: Myocardial levels of protein (modified carbonyl groups), lipid (malondialdehyde), and DNA (8-OhdG) oxidative stress biomarkers
Results: Compared to controls, atorvastatin treated animals demonstrated an increase in levels of protein oxidation (74867 +/-8420 vs. 88564+/-8202 DU* (p=0.029), lipid peroxidation (0.0313+/-.00017 vs. 0.047+/-0.004 μM MDA/μg protein (p<0.0049), and DNA oxidation (1.434+/-0.16 vs. 2.420+/-0.6 ng/mL (p=0.12). *DU=densitometry units
Conclusions: Treatment with atorvastatin can reduce biomarkers of oxidative stress in blood and urine, but its effects on the myocardium are not well studied. This investigation demonstrates increases in the oxidative stress markers of the three major targets of oxygen free radicals -protein, lipid, and DNA with atorvastatin treatment, providing insight in to a possible mechanism underlying the reduced angiogenic response seen in other studies. | Oxidative Stress Biomarker | Hypercholesterolemia | Hypercholesterolemia+Atorvastatin | p-value | | Protein (modified carbonyl group) n=8/group | 74867+/-8420 DU | 88564+/-8202 DU
DU=densitometry units | 0.029 | | Lipid (malondialdehyde) n=6/group | 0.0313+/-0.0017 μM MDA/μg protein | 0.047+/-0.004 μM MDA/μg protein | 0.0049 | | DNA (8-OhdG) n=5/group | 1.434+/-0.16 ng/mL | 2.420+/-0.6 ng/mL | 0.12 |
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