Preventive effects of pravastatin on thrombin-triggered vascular responses via Akt/eNOS and RhoA/Rac1 pathways in vivo.
OBJECTIVE
Small GTPases RhoA and Rac1 play crucial roles in endothelial dysfunction and reactive oxygen species (ROS) generation. We reported evidence that in thrombin-stimulated endothelial cells, rapid geranylgeranylation is an essential process for full activation of unprocessed RhoA, which is blocked by statin. In this study, we examined the effects of intravenous administration of pravastatin on thrombin-triggered vascular responses in vivo, as well as on the lipid modification of unprocessed forms of RhoA and Rac1 and their activation induced by thrombin.


RESULTS
Thrombin (50 U/kg) was intravenously injected with or without 0.3 mg/kg pravastatin into Wistar and spontaneously hypertensive rats. Coadministration of pravastatin prevented thrombin-induced impaired endothelium-dependent coronary vasodilation and down-regulated Akt/endothelial nitric oxide synthase (eNOS) phosphorylation within 1 h, as well as the down-regulation of eNOS protein expression within 4 h. In addition, thrombin increased Rac1/p47(phox)-dependent NAD(P)H oxidase activities of rat aortas within 1 h, resulting in ROS generation, which was prevented by the coadministration of pravastatin. Furthermore, the coadministration of pravastatin prevented thrombin-induced conversion of unprocessed RhoA and Rac1 into the geranylgeranylated forms as well as GTP-loading and membrane translocation within 1 h.


CONCLUSIONS
Intravenous injection of pravastatin prevents impaired NO-dependent vasodilation and Rac1/NAD(P)H oxidase-mediated-ROS generation by blocking the down-regulation of Akt/eNOS pathways and the full activation of unprocessed RhoA and Rac1 in vivo.
Ohkawara
Hiroshi
H
Department of Cardiology and Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Ishibashi
Toshiyuki
T
Saitoh
Shu-ichi
S
Inoue
Nobutaka
N
Sugimoto
Koichi
K
Kamioka
Masashi
M
Uekita
Hironori
H
Kaneshiro
Takashi
T
Ando
Katsuya
K
Takuwa
Yoh
Y
Maruyama
Yukio
Y
Takeishi
Yasuchika
Y
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006160:Guanosine Triphosphate / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000924:Anticholesteremic Agents; D017382:Reactive Oxygen Species; D006160:Guanosine Triphosphate; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D017035:Pravastatin