title: Simvastatin and GGTI-2133, a geranylgeranyl transferase inhibitor, increase erythrocyte deformability but reduce low O(2) tension-induced ATP release.
abstract: Statin drugs inhibit 3-hydroxy-3-methylglutaryl CoA reductase, which reduces the synthesis of both cholesterol and isoprenoids (geranylgeranyl pyrophosphate and farnesyl pyrophosphate), with the latter being lipid molecules responsible for the posttranslational modification of small GTP-binding proteins such as Rho. Effects of statins, independent of lowering blood cholesterol levels, are thought to occur by inhibition of Rho/Rho kinase. The Rho kinase inhibitor Y-27632 has been reported to increase both erythrocyte deformability and low O2 tension-induced ATP release. Here, we tested the hypothesis that by inhibiting Rho/Rho kinase, simvastatin would increase both erythrocyte deformability and low O2 tension-induced ATP release. Male Sprague-Dawley rats were divided into two groups, control or simvastatin treated [simvastatin-supplemented chow (0.02%)], for 4 wk. Simvastatin treatment increased rat erythrocyte deformability compared with controls (n = 6, P < 0.05). However, erythrocytes of simvastatin-treated rats (n = 9, P < 0.05) exhibited impaired low O2 tension-induced ATP release. Similarly, the geranylgeranyl transferase inhibitor GGTI-2133 (10 μM) also increased deformability and impaired low O2 tension-induced ATP release in healthy human erythrocytes (P < 0.05). Interestingly, ATP release in response to mastoparan 7 (n = 7, P < 0.05), which directly activates Gi, and isoproterenol (n = 5, P < 0.05), which signals through Gs, was not altered by incubation with GGTI-2133. These results suggest that although statins increase erythrocyte deformability, likely by inhibiting geranylgeranylation, the finding that both statins and a geranylgeranyl transferase inhibitor attenuated low O2 tension-induced ATP release demonstrates that factors in addition to erythrocyte deformability are critical for ATP release in response to this physiological stimulus.
authors: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. thuetk@slu.edu
authors: K M
authors: KM
authors: Clapp
authors: M L
authors: ML
authors: Ellsworth
authors: R S
authors: RS
authors: Sprague
authors: A H
authors: AH
authors: Stephenson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D004907:Erythrocyte Deformability / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010313:Partial Pressure; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D014862:Wasp Venoms / Q000494:pharmacology; D055815:Young Adult; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000924:Anticholesteremic Agents; C547856:GGTI-2133; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; D014862:Wasp Venoms; C037500:mastoparan; D000255:Adenosine Triphosphate; D002784:Cholesterol; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D054460:rho-Associated Kinases; D007930:Leucine; D007545:Isoproterenol; D010100:Oxygen