Long-term insulin treatment of vascular smooth muscle cells from rat aorta attenuates the synergistic effect of insulin on angiotensin II- and epidermal growth factor-induced DNA synthesis.
1. In the present study the effects of acute and chronic insulin treatment on growth factor-induced cell growth were investigated in vascular smooth muscle cells. Cell growth was quantified by the incorporation of [3H]thymidine into cell DNA and by determination of total protein. 2. Insulin in a concentration range of 10(-9)-10(-6) mol/l had no effect on cell DNA synthesis. Insulin-like growth factor-1 in a concentration range of 10(-9)-10(-6) mol/l induced a concentration-dependent increase in total cell protein, whereas no changes in DNA synthesis were observed. 3. Acutely, insulin enhanced the mitogenic effect of epidermal growth factor and angiotensin II. Long-term treatment with 10 and 100 ng/ml insulin over 14 weeks was associated with a time-dependent reduction in this potentiating effect of insulin on growth factor-induced DNA synthesis. To evaluate the mechanism of this effect, receptor binding studies were performed with 125I-labelled insulin-like growth factor-1. No difference in the Kd value (2.1 nmol/l) for insulin-like growth factor-1 was found between untreated and chronically insulin-treated cells, whereas the maximal number of binding sites decreased from 5.9 x 10(4) (untreated cells) to 4.7 x 10(4) (10 ng/ml) and to 4.3 x 10(4) (100 ng/ml) binding sites/cell in chronically insulin-treated cells. 4. We conclude that insulin acutely enhances the mitogenic effect of various growth factors such as epidermal growth factor and angiotensin II on vascular smooth muscle cells. Long-term insulin treatment reduced the number of receptor binding sites for insulin-like growth factor-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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Medizinische Universitäts-Poliklinik, Bonn, Federal Republic of Germany.
Nettekoven
W
W
Christian
R
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Wieczorek
A J
AJ
Düsing
R
R
Vetter
H
H
Sachinidis
A
A
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D007328:Insulin / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D017526:Receptor, IGF Type 1 / Q000187:drug effects; D013268:Stimulation, Chemical; D013997:Time Factors
D007328:Insulin; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D004247:DNA; D017526:Receptor, IGF Type 1