Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction.
Angiotensin II (Ang II) increases atherosclerotic cardiovascular disease. Renal damage that is characterized by activation of Ang II markedly potentiates the risk for atherosclerosis, even in the setting of subtle renal impairment. Therefore, whether antagonism of Ang II actions can modify atherosclerosis in a model of mild renal impairment was examined. Apolipoprotein E-deficient spontaneously hyperlipidemic mice underwent uninephrectomy (UNx) or sham operation (sham) followed by treatment with Ang II receptor antagonist losartan or hydralazine for 12 wk. While UNx did not increase the serum creatinine levels, BP and lipids were higher in UNx mice than in age-matched sham controls with intact kidneys. UNx caused a dramatic increase in the extent and the number of atherosclerotic lesions together with greater macrophage-positive area and more disruption in the elastin component of the extracellular matrix versus sham. Ang II antagonism dramatically decreased the UNx-induced acceleration in atherosclerosis in association with decreased macrophage content, linked to decreased macrophage migration in vitro with losartan but not with hydralazine. Aortae of mice treated with Ang II antagonism had fewer elastin breaks together with less immunostaining for the powerful elastolytic enzyme cathepsin S. None of these benefits was observed in the hydralazine-treated mice despite equivalent reduction in BP. These findings support an important role for endogenous Ang II in accelerated atherosclerosis in renal dysfunction and offer a therapeutic intervention with particular benefit in this setting through mechanisms that include reduced vascular macrophage infiltration and preservation of the elastin component of extracellular matrix.
Suganuma
Eisuke
E
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Zuo
Yiqin
Y
Ayabe
Nobuhiko
N
Ma
Ji
J
Babaev
Vladimir R
VR
Linton
Macrae F
MF
Fazio
Sergio
S
Ichikawa
Iekuni
I
Fogo
Agnes B
AB
Kon
Valentina
V
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006830:Hydralazine / Q000627:therapeutic use; D019808:Losartan / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D051437:Renal Insufficiency / Q000150:complications* / Q000378:metabolism / Q000473:pathology
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D006830:Hydralazine; D002784:Cholesterol; D003404:Creatinine; D019808:Losartan