Preservation of vascular DDAH activity contributes to the protection of captopril against endothelial dysfunction in hyperlipidemic rabbits.
Endothelial dysfunction plays a pivotal role in the pathogenesis of atherosclerosis. Endogenous inhibitor of nitric oxide synthase (NOS) asymmetric dimethylarginine (ADMA) has been recognized as an independent risk factor of endothelial dysfunction and the biomarker of atherosclerosis. This study was to investigate whether endogenous ADMA and its metabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH) were involved in mechanisms of captopril protection against endothelial dysfunction in high fat diet feeding rabbits. Half of model rabbits were treated with captopril (10mg/kg/d, i.g.) for 12w. Vascular morphology and serum lipid profiles were detected. Serum ADMA concentration were assayed by high performance liquid chromatography. Recombinant DDAH2 gene adenoviruses were ex vivo transferred to thoracic aortas of high fat diet feeding rabbits. Endothelium-dependent relaxation of aortas response to acetylcholine and DDAH activity were measured. Atherosclerosis was confirmed in high fat diet feeding rabbits by increased serum lipid profiles and morphologic changes of vascular wall. Serum ADMA levels were significantly increased in hyperlipidemic rabbits accompanied with impairment of endothelium-dependent relaxation and inhibition of DDAH activity in thoracic aortas. Captopril treatment not only decreased vascular intima thickening and serum ADMA concentration but also preserved vascular DDAH activity and endothelium-dependent relaxation in hyperlipidemic rabbits without influence on serum lipid profiles. Similar beneficial effects on endothelial function and DDAH activity could be achieved by DDAH2 gene transfection. These results indicated that captopril could protect against injuries of vascular morphology and endothelial function in hyperlipidemic rabbits, the mechanisms may be related to the preservation of DDAH activity and decrease of ADMA accumulation in vascular endothelium.
Department of Pharmacology, Guangzhou Institute of Snake Venom Research, Guangzhou Medical University, Guangzhou 511436, Guangdong, PR China.
Yuan
Y
Lin
Department of Pharmacology, Guangzhou Institute of Snake Venom Research, Guangzhou Medical University, Guangzhou 511436, Guangdong, PR China.
Mei
M
Feng
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, Hunan, PR China.
Chang-Wu
CW
Lu
Department of Pharmacology, Guangzhou Institute of Snake Venom Research, Guangzhou Medical University, Guangzhou 511436, Guangdong, PR China.
Yan-Ping
YP
Lei
Department of Pharmacology, Cancer Research Institute, Cancer Hospital, Guangzhou Medical University, Guangzhou 510095, Guangdong, PR China.
Zhi-Min
ZM
He
Department of Pharmacology, Guangzhou Institute of Snake Venom Research, Guangzhou Medical University, Guangzhou 511436, Guangdong, PR China; Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, Hunan, PR China. Electronic address: Xiongyan2001@yahoo.com.
Yan
Y
Xiong
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D002216:Captopril / Q000494:pharmacology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006949:Hyperlipidemias / Q000097:blood / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011817:Rabbits
D004791:Enzyme Inhibitors; C018524:N,N-dimethylarginine; D001120:Arginine; D002216:Captopril; D000581:Amidohydrolases; C059999:dimethylargininase
Asymmetric dimethylarginine; Captopril; Dimethylarginine dimethylaminohydrolase; Endothelial dysfunction; Hyperlipidemia