Simvastatin reduces mortality and hepatic injury after hemorrhage/resuscitation in rats.
Statins are established in the prevention and therapy of chronic cardiovascular diseases because of inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A), thus lowering blood cholesterol levels. However, their cholesterol-independent effects include regulation of Rho/Rho-kinases (ROCK) and eNOS, proteins centrally involved in various models of acute inflammation. Therefore, we tested the hypothesis that simvastatin confers protection after rat hemorrhage/resuscitation (H/R) and wanted to elucidate the mechanisms involved. Fifty-two female Lewis rats (180-250 g) were pretreated with simvastatin 5 mg/kg per day or vehicle for 6 days (i.p.). Then, rats were hemorrhaged to a mean arterial pressure of 30 +/- 2 mmHg for 60 min and resuscitated. Control group underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested. Mortality was assessed 72 h after H/R. Simvastatin pretreatment increased survival after H/R from 20% to 80%. Serum alanine aminotransferase after H/R increased 2.2-fold in vehicle as compared with simvastatin-treated rats. Histopathological analysis revealed decreased hepatic necrosis in simvastatin-treated rats after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress, inflammatory markers (serum IL-6 and hepatic infiltration with polymorphonuclear leukocytes), and actin cytoskeleton rearrangements were decreased after simvastatin pretreatment compared with vehicle-treated rats after H/R. Simvastatin increased eNOS and heme oxygenase 1 expression and eNOS activation. Expression of Rho/Rho-kinase and myosin phosphatase targeting subunit, Thr-MYPT1, a marker for Rho-kinase activity, decreased after simvastatin treatment compared with vehicle-treated rats after H/R. Simvastatin pretreatment exerts beneficial effects in this model of acute inflammation by supporting protective mechanisms that are important for hepatic microcirculation after H/R.
Relja
Borna
B
Departments of Trauma SurgeryJohann Wolfgang Goethe University Frankfurt am Main, Frankfurt, Germany.
Lehnert
Mark
M
Seyboth
Korbinian
K
Bormann
Fabian
F
Höhn
Christoph
C
Czerny
Christoph
C
Henrich
Dirk
D
Marzi
Ingo
I
D000199:Actins / Q000378:metabolism; D000447:Aldehydes; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000166:cytology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D012151:Resuscitation / Q000009:adverse effects*; D019821:Simvastatin / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives
D000199:Actins; D000447:Aldehydes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; C002744:3-nitrotyrosine; D014443:Tyrosine; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C027576:4-hydroxy-2-nonenal