P136Farnesol treatment decreases infarct size in rat hearts

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Abstract

Purpose

We have previously shown that the beneficial effect of preconditioning on ischemic myocardial function was recaptured by farnesol (a key metabolite of the mevalonate pathway) in the heart of cholesterol fed rats. Farnesol is also known as an antioxidant. Our aim was to examine whether farnesol treatment decreases infarct size in rats fed with normal rat chow and modulates the activity of the mevalonate pathway and/or cardiac oxidative/nitrosative stress.

Methods

Male Wistar rats were treated with oral administration of 0.2, 1, 5, and 50 mg/kg/day farnesol or its solvent for 12 days, respectively. On day 13, isolated perfused hearts were subjected to 30 min coronary occlusion followed by 120 min reperfusion. At the end of reperfusion, infarct size was determined. In separate experiments, basal cardiac level of mevalonate pathway derivates (Q9, Q10, cholesterol, prenylated proteins), and 3-nitrotyrosine (marker of oxidative/nitrosative stress) were measured following the 12-day farnesol pretreatment.

Results

We found that 1 mg/kg/day farnesol pretreatment significantly decreased infarct size (22.3 ± 3.9% vs. 40.0 ± 4.1%, p < 0.05). However, 0.2, 5, and 50 mg/kg/day farnesol remained ineffective (37.3 ± 5.1%, 31.9 ± 3.1%, 43.5 ± 5.1% vs. 40.0 ± 4.1%, respectively). The effective dose of farnesol significantly increased cardiac N-acetyl-S-geranylgeranyl-L-cysteine level (96.8 ± 11.1 vs. 56.0 ± 9.0 ng/mg tissue, p < 0.05), but did not influence cardiac N-acetyl-S-farnesyl-L-cysteine level (21.4 ± 1.5 vs. 30.7 ± 5.9 ng/mg tissue). One mg/kg/day farnesol significantly increased cardiac cholesterol level (0.73 ± 0.02 vs. 0.56 ± 0.04 μg/g tissue p < 0.05), and caused a non-significant increase in cardiac coenzyme Q9 and Q10 levels (94.79 ± 6.14 vs. 68.91 ± 16.48 μg/g tissue, 6.46 ± 0.52 vs. 5.46 ± 1.02 μg/g tissue, respectively). Cardiac 3-nitrotyrosine level was modified significantly only by the highest dose 50 mg/kg/day farnesol (1.16 ± 0.18 vs. 2.44 ± 0.47 ng/mg protein, p < 0.05).

Conclusion

Farnesol dose-dependently decreased infarct size and 1 mg/kg/day farnesol was the most effective dose. We conclude that the infarct size limiting effect of farnesol likely involves increased protein geranylgeranylation and seems to be independent of the antioxidant effect of farnesol.

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