Angiotensin II induces c-fos mRNA in aortic smooth muscle. Role of Ca2+ mobilization and protein kinase C activation.
Vasoconstrictors such as angiotensin II (Ang II) play an important role in the pathogenesis of hypertension. These agonists may be responsible for the abnormal vascular smooth muscle cell (VSMC) growth seen in hypertension, either indirectly as a consequence of elevating blood pressure or directly as a result of receptor-mediated effects on VSMC growth. To investigate whether Ang II might directly initiate or modulate some of the "early" genetic programs associated with growth in VSMC, the expression of the proto-oncogene c-fos was studied in cultured rat aortic VSMC. Ang II rapidly induced the accumulation of c-fos mRNA, with maximal levels occurring at approximately 30 min. Induction of c-fos mRNA by Ang II was concentration-dependent, with a maximal response at 100 nM. Ang II induction of c-fos mRNA was blocked by its competitive inhibitor, [sarcosine 1,isoleucine 8]angiotensin II. Induction of c-fos mRNA was not dependent upon Ang II-stimulated intracellular alkalinization or activation of Na+/H+ exchange, but was dependent upon mobilization of intracellular Ca2+ and protein kinase C activation. Epidermal growth factor, a VSMC mitogen, also induced c-fos mRNA in VSMC, but by a mechanism different from that of Ang II. These results demonstrate that the vasoconstrictor hormone Ang II induces in VSMC one of the earliest genes, c-fos, associated with the proliferative response.
Taubman
M B
MB
Department of Cardiology, Children's Hospital, Boston, Massachusetts.
Berk
B C
BC
Izumo
S
S
Tsuda
T
T
Alexander
R W
RW
Nadal-Ginard
B
B
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D011519:Proto-Oncogenes / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014158:Transcription, Genetic / Q000187:drug effects*
D012333:RNA, Messenger; D000804:Angiotensin II; D011493:Protein Kinase C; D002118:Calcium