Mechanism of agonistic angiotensin Ⅱ type Ⅰ receptor autoantibody-amplified contractile response to Ang Ⅱ in the isolated rat thoracic aorta

Agonistic autoantibody to the angiotensin Ⅱ type Ⅰ receptor （AT1-AA） is highly associated with preeclampsia by increasing the sensitivity of Ang Ⅱ during pregnancy in rats, thus leading to a preeclampsia-like syndrome. However, the mechanism underlying this phenomenon remains unclear. The purpose of this study was to observe AT1-AA amplification of Ang Ⅱ-induced vasocon- striction in rat thoracic aortic rings. It was found that exposure to low concentrations of AT1-AA （0.4 nM） caused a contraction of 〈5% of the maximal response to 60 mM KCI. In addition, the Ang Ⅱ-induced contractile response was amplified in the presence of a threshold contraction to AT1- AA, as manifested by a leftward shift of the midpoint of the concentration-response curve with no change in the maximal response. These results showed that preincubation with low AT1-AA could amplify the Ang Ⅱ dose-response curve, and this amplification could be attenuated markedly by 0.1 μM heptapeptide AFHYESQ. In calcium-free Krebs solution, 10 μM of 2-aminoethoxydiphenyl borate （an IP3 receptor inhibitor） both blocked the AT1-AA base contraction and completely abolished the amplification. Both 5 μM of U-73122 （a phospholipase C inhibitor） and 10μM of εV1-2 （an εPKC inhibitor） could partially inhibit the Ang Ⅱ-induced contractile response. εV1-2, but not U-73122, could completely inhibit the amplification response of AT1-AA to Ang Ⅱ. These results suggest that AT1-AA is able to cause amplification response to Ang Ⅱ probably via the calcium-independent protein kinase C pathway, which may provide a new therapy strategy for preeclampsia.