Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition.
Angiotensin (Ang) II is capable of producing inflammatory changes by signals through its AT1 receptor. Reactive oxygen species production, adhesion molecule expression, chemokines, and other mediators are involved. Nuclear factor-kappaB (NK-kappaB) and activator protein 1 (AP-1) are two of the transcription factors activating the responsible genes. We have studied Ang II-independent modulating effects in a double transgenic rat model harboring the human renin and angiotensinogen genes. We have recently focused on the protective effects of HMG-CoA reductase inhibition and review these data here. We found that cerivastatin decreased mortality, lowered blood pressure, preserved renal function, decreased cardiac hypertrophy, and inhibited the entire chain of inflammatory events. Furthermore, NF-kappaB and AP-1 activation was sharply attenuated. We also observed that cerivastatin blocked ERK1/2 phosphorylation in vivo and in vitro. Cerivastatin also inhibited phorbol ester-transmitted events in vascular smooth muscle cells. Because Rho, a member of the Ras protein superfamily is important to Ang II-dependent and -independent vascular smooth muscle signaling events, we suggest that cerivastatin may act by inhibiting the prenylation, membrane anchoring, and subsequent activation of Ras proteins. These data may in part explain cholesterol-independent, HMG-CoA reductase-related, protective effects.
Dechend
R
R
Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Fiebler
A
A
Lindschau
C
C
Bischoff
H
H
Müller
D
D
Park
J K
JK
Dietz
R
R
Haller
H
H
Luft
F C
FC
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D006321:Heart / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000209:etiology* / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D000804:Angiotensin II; C086276:cerivastatin