Position of Src tyrosine kinases in the interaction between angiotensin II and endothelin in in vivo vascular protein synthesis.
OBJECTIVE
Endothelin is a necessary intermediate in the trophic action of angiotensin II during hypertension-induced resistance artery remodeling in vivo. Since Src tyrosine kinases can be activated by both agonists, we studied their role in the trophic action of angiotensin II, endothelin and their interaction in rat small mesenteric arteries.


RESULTS
Twenty-six hour infusion of high-dose angiotensin II (400 ng/kg per min) or endothelin (5 pmol/kg per min) via osmotic pumps significantly enhanced vascular protein synthesis in vivo. When angiotensin II was used as the trophic stimulus, treatment with a Src tyrosine kinase inhibitor (PP2, 0.5 mg/kg, starting at 21 h of the 26-h stimulation) produced a significant attenuation of extracellular regulated kinase 1 (ERK 1) phosphorylation and of protein synthesis. However, PP2 administered at 21 h or throughout the 26-h infusion did not abrogate the elevation of protein synthesis induced by endothelin. Moreover, endothelin did not enhance the phosphorylation of ERK 1/2 in small mesenteric arteries. We confirmed that angiotensin II stimulated the expression of prepro-endothelin mRNA in small mesenteric arteries in a Src-dependent manner, as the response was inhibited by PP2. To support the specific inhibitory activity of PP2 on Src tyrosine kinases in vivo, angiotensin II-induced phosphorylation of cortactin, a Src-specific substrate, was inhibited by PP2.


CONCLUSIONS
Src tyrosine kinases represent an important signaling element in angiotensin II-induced endothelin production in small arteries in vivo. However, Src tyrosine kinases did not appear to contribute to the trophic signaling of endothelin, suggesting that they lie upstream of endothelin in the angiotensin II-endothelin-protein synthesis cascade.
Beaucage
Pierre
P
Faculté de pharmacie, Université de Montréal, Montreal, Quebec, Canada. pierre.moreau@umontreal.ca
Iglarz
Marc
M
Servant
Marc
M
Touyz
Rhian M
RM
Moreau
Pierre
P
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014655:Vascular Resistance; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D000804:Angiotensin II; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3