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|Title:||Angiotensin II responses of vascular smooth muscle cells from hypertensive rats: enhancement at the level of p42 and p44 mitogen activated protein kinase.|
|Citation:||BR J PHARMACOL, 1997, 122 (2), pp. 209-216|
|Abstract:||1. Stimulation of the AT1 receptor by angiotensin II (AII) gives a larger mitogenic response in vascular smooth muscle cells from spontaneously hypertensive rats (SHR) compared to those from normotensive (WKY) controls. Here we investigated whether the p42 and p44 mitogen activated protein kinase (MAPK) pathway is differentially regulated in these cells by AT1 receptors. 2. We showed that there is a similar level of p42 and p44 MAPK immunoreactivity in the SHR and WKY derived cells. 3. However, by use of an antiserum specific for the tyrosine phosphorylated form of MAPK, and an assay with a nonapeptide MAPK substrate, we showed that AII (100 nM)-stimulated phosphorylation and activation of p42mapk and p44mapk are enhanced in the SHR derived cells. 4. This increased MAPK activity in SHR derived cells was also seen on protein kinase C activation with 100 nM phorbol myristate acetate (PMA). The size and time course of the response to PMA was the same as that to AII in each cell type. 5. The protein kinase C inhibitor Ro 31-8220 attenuated the early (2 min) phase of AII stimulation of MAPK activity and the entire stimulation caused by PMA. At longer times of AII stimulation both p42mapk and p44mapk were activated by an Ro 31-8220-insensitive mechanism. 6. Agonist or PMA stimulation of MAPK activity was inhibited by the tyrosine kinase inhibitor genistein. AII stimulated tyrosine protein phosphorylation to a greater degree in SHR than WKY cells. 7. These results show that the MAPK response of SHR derived cells is increased over that of WKY cells by mechanisms independent of the enhanced stimulation of phospholipase C; amplification at the level of sequential protein kinase C and tyrosine kinase steps leads to the enhanced responsiveness of MAPK in the SHR derived cells.|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
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