Differential activation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen activated-protein kinase by AT(1) receptors in vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats

Objectives The present study investigates effects of angiotensin II on acti vation of extracellular signal-regulated protein kinase (ERK)1/2, p38 mitog en activated-protein kinase (p38MAPK) and c-Jun amino terminal kinase (JNK) in vascular smooth muscle cells from spontaneously hypertensive rats (SHR) , Methods Vascular smooth muscle cells (VSMC) from mesenteric arteries of Wis tar- Kyoto (WKY) rats and SHR were studied. Angiotensin II-induced phosphor ylation of ERK1/2, JNK and p38MAPK were assessed by Western blot analysis. c-fos mRNA expression by angiotensin II was determined by reverse transcrip tase-polymerase chain reaction in the absence and presence of PD98059, sele ctive inhibitor of ERK1/2-dependent pathways and S8202190, selective p38MAP K inhibitor. Results Angiotensin II increased phosphorylation of ERK1/2 and p38MAPK, but not JNK. Responses were significantly increased in SHR compared with WKY, Irbesartan, AT(1) receptor antagonist, but not PD123319, AT(2) receptor blo cker, abolished angiotensin Ii-induced effects. PP2, selective Src inhibito r, decreased angiotensin II-mediated activation of MAP kinases, Angiotensin II increased c-fos mRNA expression in SHR and had a small stimulatory effe ct in WKY. These actions were inhibited by PD98059, whereas S8202190 had no effect. Conclusions Angiotensin II-induced activation of vascular ERK1/2 and p38MAP K is increased in SHR, These effects are mediated via AT(1) receptors, whic h activate Src-dependent pathways. Overexpression of c-fos mRNA in SHR is d ue to ERK1/2-dependent, p38MAPK-independent pathways. Our results suggest t hat angiotensin II activates numerous MAP kinases in VSMCs and that differe ntial activation of these kinases may be important in altered growth signal ing in VSMCs from SHR.