Angiotensin II Induces c-fos mRNA in Aortic Smooth Muscle: Role of Ca2+ mobilization and protein kinase C activation

M B Taubman,B C Berk,S Izumo,T Tsuda,R W Alexander,B Nadal-Ginard

doi:10.1016/s0021-9258(17)31290-5

M B Taubman, B C Berk + Show 4 more

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https://doi.org/10.1016/s0021-9258(17)31290-5

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Abstract

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.

Highlights

Vasoconstrictors suchas angiotensin I1 (Ang 11)play strips [8, 9] and share vasoconstrictor properties with an important role in the pathogeneosfishypertension
Exposure of vascular smooth muscle cell (VSMC) growth seen in quiescent rat aortic VSMC cultures to AngI1 (100 nM) or hypertension,eitherindirectly as a consequence of PDGF (2.5 ng/ml) for 24 h results in a 60-80% increase in elevating blood pressure or directalys a result of receptor-mediated effects on VSMC growth
To investigate whether Ang I1 might directlyinitiateormodulate some of the “early”genetic programs associated with growth inVSMC, the expression of the proto-oncogene c-fos was studied in culturerdat aorticVSMC

Summary

THEJOURNALOF BIOLOGICACLHEMISTRY

0 1989by The American Society for Biochemistry and Molecular Biology, Inc. Vol 264,No 1,Issue of January 5, pp. 526530,1989 Printed in U.S.A. It would be important to ascertain which zation of intracellular Ca2+ and protein kinaCseacti- transcriptional eventsassociated with cell division are shared vation.Epidermalgrowthfactor, a VSMC mitogen, by both AngI1 and PDGF and at what point(s) along the induced c-fomsRNA in VSMC, but by a mechanism cascade of gene activation associated with mitogenesis diverdifferent from that of Ang 11. These results demonstrate that thevasoconstrictor hormoneAng I1 induces in VSMC one of the earliest genes, c-fos, associated with the proliferativeresponse. The abbreviations used are: VSMC, vascular smooth muscle cells; Ang 11, angiotensin 11; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; DME, Dulbecco’s modified Eagle’s medium; MOPS, 4-morpholinepropanesulfonic acid; Hepes, 4-(2-hydroxy-

MATERIALS AND METHODS

Findings

The relationship between contractile agonists such as Ang