Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition

Angiotensin (Ang) II is capable of producing inflammatory changes by signal s through its AT1 receptor. Reactive oxygen species production, adhesion mo lecule expression, chemokines, and other mediators are involved. Nuclear fa ctor-kappaB (NK-kappaB) and activator protein 1 (AP-I) are two of the trans cription factors activating the responsible genes. We have studied Ang II-i ndependent modulating effects in a double transgenic rat model harboring th e human renin and angiotensinogen genes. We have recently focused on the pr otective effects of HMG-CoA reductase inhibition and review these data here . We found that cerivastatin decreased mortality, lowered blood pressure, p reserved renal function, decreased cardiac hypertrophy, and inhibited the e ntire chain of inflammatory events. Furthermore, NF-kappaB and AP-1 activat ion was sharply attenuated. We also observed that cerivastatin blocked ERK1 /2 phosphorylation in vivo and in vitro. Cerivastatin also inhibited phorbo l 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 ceriv astatin may act by inhibiting the prenylation, membrane anchoring, and subs equent activation of Ras proteins. These data may in part explain cholester ol-independent, HMG-CoA reductase-related, protective effects. Am J Hyperte ns 2001;14:55S-61S (C) 2001 American Journal of Hypertension, Ltd.