HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase.
Hypertension is associated with endothelial dysfunction and increased cardiovascular risk. Caveolin-1 regulates nitric oxide (NO) signaling by modulating endothelial nitric oxide synthase (eNOS). The purpose of this study was to examine whether HMG-CoA reductase inhibitor improves impaired endothelial function of the aorta in spontaneous hypertensive rat (SHR) and to determine the underlying mechanisms involved. Eight-week-old male SHR were assigned to either a control group (CON, n=11) or a rosuvastatin group (ROS, n=12), rosuvastatin (10 mg/kg/day) administered for eight weeks. Abdominal aortic rings were prepared and responses to acetylcholine (10(-9)-10(-4) M) were determined in vitro. To evaluate the potential role of NO and caveolin-1, we examined the plasma activity of NOx, eNOS, phosphorylated-eNOS and expression of caveolin-1. The relaxation in response to acetylcholine was significantly enhanced in ROS compared to CON. Expression of eNOS RNA was unchanged, whereas NOx level and phosphorylated-eNOS at serine-1177 was increased accompanied with depressed level of caveolin-1 in ROS. We conclude that 3-Hydroxy-3-methylglutaryl Coenzyme-A (HMG-CoA) reductase inhibitor can improve impaired endothelial dysfunction in SHR, and its underlying mechanisms are associated with increased NO production. Furthermore, HMG-CoA reductase inhibitor can activate the eNOS by phosphorylation related to decreased caveolin-1 abundance. These results imply the therapeutic strategies for the high blood pressure-associated endothelial dysfunction through modifying caveolin status.
Suh
Jung-Won
JW
Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
Choi
Dong-Ju
DJ
Chang
Hyuk-Jae
HJ
Cho
Young-Seok
YS
Youn
Tae-Jin
TJ
Chae
In-Ho
IH
Kim
Kwang-Il
KI
Kim
Cheol-Ho
CH
Kim
Hyo-Soo
HS
Oh
Buyng-Hee
BH
Park
Young-Bae
YB
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D051242:Caveolin 1 / Q000378:metabolism*; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D051242:Caveolin 1; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine