Simvastatin reverses the hypertension of heterozygous mice lacking cystathionine beta-synthase and apolipoprotein A-I.
Double heterozygous mice lacking Apoa1 and Cbs genes show mild hyperhomocysteinemia in combination with hypoalphalipoproteinemia. This situation leads to a moderate hypertension associated with a dysregulation in nitric oxide metabolism. The aim of this study was to investigate the potential beneficial effects of statin treatment in these mice. After 4 weeks of simvastatin administration, plasma parameters; apolipoproteins A-I, A-II and A-IV; lipid profile; and blood pressure were assessed, Western blotting was performed in the aorta of these mice to measure endothelial nitric oxide synthase and caveolin-1 content. The high blood pressure level present in the double heterozygous group was corrected down to that of the wild-type group after simvastatin treatment (124+/-7.7 vs. 109+/-11.2 mmHg, p<0.01). Concomitant with this effect, an increase in nitric oxide levels was observed in these double heterozygous mice receiving simvastatin treatment probably mediated in part by a decrease in caveolin-1 levels. Blood pressure changes appeared to be independent of the arylesterase activity of paraoxonase or the lipid content. Another remarkable result was the significant increase in apoA-IV content in animals receiving simvastatin, an effect considered to be protective for the endothelium. In conclusion, the results of this study demonstrate that the use of simvastatin can improve blood pressure control in mice with elevated homocysteinemia and low levels of apoA-I, and this effect is mediated by mechanisms independent of plasma lipids and related to nitric oxide levels.
Carnicer
Ricardo
R
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto Aragonés de Ciencias de la Salud, Universidad de Zaragoza-Dirección Salud del Gobierno de Aragón, Zaragoza, Spain.
Navarro
María A
MA
Guillén
Natalia
N
Arbonés-Mainar
José M
JM
Surra
Joaquín C
JC
Acín
Sergio
S
Osada
Jesús
J
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000235:genetics*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002853:Chromatography, Liquid; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006579:Heterozygote; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D019821:Simvastatin / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D016632:Apolipoprotein A-I; D008074:Lipoproteins; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D019821:Simvastatin; D003541:Cystathionine beta-Synthase