D1-like receptors inhibit insulin-induced vascular smooth muscle cell proliferation via down-regulation of insulin receptor expression.
OBJECTIVE
Vascular smooth muscle cell (VSMC) proliferation is central to the development of vascular diseases, including hypertension, which is regulated by numerous hormones and humoral factors. Our previous study showed that the stimulatory effect of norepinephrine on VSMC proliferation is inhibited by D1-like receptors and the D3 dopamine receptor, a member of the D2-like receptor family. Insulin is a proliferative hormone but it is not known if there is any interaction between insulin and D1-like receptors. We hypothesized that Dl-like receptors may have an inhibitory effect on the insulin-induced VSMC proliferation; aberrant insulin and Dl-like receptor functions could be involved in the pathogenesis of essential hypertension.


METHODS
VSMC proliferation was determined by [H]-thymidine incorporation; insulin receptor mRNA and protein expressions were determined by RT-PCR, immunoblotting, and immunohistochemistry.


RESULTS
Insulin increased VSMC proliferation in immortalized aortic A10 cells, determined by [H]-thymidine incorporation. Although the D1-like receptor, by itself, had no effect on VSMC proliferation, stimulation with fenoldopam, a D1-like receptor agonist, inhibited the stimulatory effect of insulin. The inhibitory effect of fenoldopam on insulin-mediated VSMC proliferation was receptor specific, because its effect could be blocked by SCH23390, a D1-like receptor antagonist. Fenoldopam also inhibited insulin receptor mRNA and protein expression, which was time dependent and concentration dependent. A PKC or MAP kinase inhibitor blocked the inhibitory effect of fenoldopam on insulin receptor expression, indicating that PKC and MAP kinase were involved in the signaling pathway.


CONCLUSIONS
The inhibitory effect of D1-like receptors on insulin-mediated VSMC proliferation may play an important role in the regulation of blood pressure.
Zeng
Chunyu
C
Department of Cardiology, Daping Hospital, Chongqing, PR China. cyzeng1@hotmail.com
Han
Yu
Y
Huang
Hefei
H
Yu
Changqing
C
Ren
Hongmei
H
Shi
Weibin
W
He
Duofen
D
Huang
Lan
L
Yang
Chengming
C
Wang
Xukai
X
Zhou
Lin
L
Jose
Pedro A
PA
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000196:embryology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D018818:Fenoldopam / Q000494:pharmacology; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D013997:Time Factors
D007328:Insulin; D017447:Receptors, Dopamine D1; D011972:Receptor, Insulin; D018818:Fenoldopam