Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation

Abstract

Postconditioning (POC) reduces lethal reperfusion injury under normal conditions, but its effectiveness under certain pathological states is in dispute. In the present study, we sought to determine the effect of chronic simvastatin treatment in hyperlipidemic animals with or without POC. Anesthetized rabbits were randomized into eight groups, as follows, and were subjected to 30-min myocardial ischemia followed by 3-h reperfusion. Normally fed animals: a Control group with no additional intervention, a Sim group treated with simvastatin for 3 weeks at a dose of 3 mg kg(-1), a POC group subjected to POC with eight cycles of 30-s ischemia/reperfusion, a Sim-POC group treated with simvastatin, and POC. Cholesterol fed (6 weeks) animals: a Chol group with no additional interventions, a Chol-Sim group treated with simvastatin for 3 weeks, a Chol-POC group subjected to POC, and a Chol-Sim-POC group treated with simvastatin and POC. Infarct size and plasma levels of malondialdehyde (MDA), nitrotyrosine (NT), NOx, total cholesterol, and LDL were evaluated. In a second series of experiments, heart tissue samples were taken for MDA, NT, and NOx assessment. Infarct size, circulating MDA, NT, NOx and cardiac MDA, NT, and NOx levels declined in POC and all Sim groups compared with Control, Chol, and Chol-POC (p < 0.05). Simvastatin also reduced total cholesterol and LDL plasma levels. In conclusion, a 3-week simvastatin treatment limits the infarct size and attenuates the oxidative and nitrosative stress both in normo- and in hyper-cholesterolemic rabbits subjected to ischemia-reperfusion irrespective of the presence of POC, while POC is effective only in normocholesterolemic animals.

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

“…Furthermore, Iliodromitis et al (81) and Wang et al (192) suggest that PostC may reduce ONOO -formation. In particular, Iliodromitis et al (81) report that PostC reduces myocardial and circulating levels of 3-nitrotyrosine after 10 min of reperfusion in the normal, but not in the hyperlipidemic rabbits. We have shown in rat hearts that, after 7 min of reperfusion, PostC induces an increase in S-nitrosylation of proteins and a reduction in 3-nitrotyrosine levels (150).…”

“…Notably in humans, PostC has long-term protective effects (86). The infarct size reduction by ischemic PostC depends on duration of the index-ischemia, on the number and duration of the brief re-occlusions, and=or on the presence of comorbidities (81,148,174). Further studies should resolve the difference in efficacy of PostC between experimental models and human subjects with comorbidities and=or aging (40,149,155,190).…”

“…However, hyperlipidemia enhances preischemic levels of ONOO - (133), but alters the PostC-induced ONOO -formation and blocks the protective effect (99). Furthermore, Iliodromitis et al (81) and Wang et al (192) suggest that PostC may reduce ONOO -formation. In particular, Iliodromitis et al (81) report that PostC reduces myocardial and circulating levels of 3-nitrotyrosine after 10 min of reperfusion in the normal, but not in the hyperlipidemic rabbits.…”

“…We have shown in rat hearts that, after 7 min of reperfusion, PostC induces an increase in S-nitrosylation of proteins and a reduction in 3-nitrotyrosine levels (150). To reconcile these apparent opposing results (81,99,150,192) we can speculate that after an initial increase in ONOO -, a further increase in NO (via enzymatic and nonenzymatic processes (213)) can lead to the formation of N 2 O 3 , thus lowering ONOO -level and increasing S-nitrosylation (see also below). In fact, a decrease in ONOO -levels in the presence of excess NO may be due to the secondary chemical interactions occurring between NO and ONOO - (164).…”

Postconditioning the Heart: Analysis of Experimental and Clinical Data

“…Шесть сеансов реперфузии-ишемии способ-ствовали снижению индекса ЗИ/ОР в 2,4 раза у обычных кроликов, но не оказывали влияния на размер некроза у кроликов с атеросклерозом [3]. Эти данные были вновь подтверждены теми же учеными в более позднем исследо-вании [4]. Кроме того, кардиологи установили, что курсо-вое введение симвастатина обеспечивает восстановление инфаркт-лимитирующего эффекта посткондиционирова-ния у кроликов с атеросклерозом [4].…”