Anti‐atherosclerotic effects of the hexapeptide angiotensin IV

We have previously demonstrated a vasoprotective effect following two week infusion of the hexapeptide fragment, angiotensin (Ang) IV in large conduit vessels taken from apolipoprotein E‐deficient (ApoE −/− ) mice. However, the anti‐atherosclerotic potential of Ang IV to date has been inconclusive. The aim of the current study was to investigate whether the vasoprotection evoked by Ang IV could translate into an anti‐atherosclerotic effect following prolonged chronic infusion. In contrast to previous studies, Ang IV (0.72mg/kg/day) was chronically infused in ApoE −/− mice for four weeks as opposed to two, and consistent with previous studies, Ang IV evoked a significant improvement in endothelial function compared to vehicle treated animals (R max 89.6 ± 2.7% vs 71.8 ± 3.4%, P<0.05). This appeared to be an AT 4 R‐ or AT 2 R‐mediated effect as co‐infusion with either antagonists, divalinal‐Ang IV or PD123319 respectively, resulted in an abrogated response. However, four week infusion of Ang IV strikingly prevented the progression of lesion development, examined using oil red O staining in the aortic arch and thoracic aorta. Again this effect was attenuated following co‐treatment with either AT 4 R or AT 2 R antagonists. Consistent with previous studies, chronic infusion with Ang IV also resulted in an increase in endothelial nitric oxide synthase protein immunoreactivity and a concomitant decrease in superoxide assessed using dihydroethidium staining, suggesting an increase in nitric oxide bioavailability. Therefore we have now demonstrated an anti‐atherogenic effect that is mediated by Ang IV via the AT 2 R and AT 4 R and appears to counter‐regulate the atherogenic profile of Ang II. Research supported by that National Health and Medical Research Council Project Grant #436823