© 2000 American Heart Association, Inc.
Molecular Medicine |
Hyperinsulinemia Enhances Transcriptional Activity of Nuclear Factor-
B Induced by Angiotensin II, Hyperglycemia, and Advanced Glycosylation End Products in Vascular Smooth Muscle Cells
From the Department of Medicine and Research Service of the Denver VA Medical Center and University of Colorado Health Sciences Center (I.G., M.L.G., P.W., B.D.), Denver, Colo, and Department of Medicine (M.B.), Albert Einstein College of Medicine, Bronx, NY.
Correspondence to Dr Boris Draznin, VA Medical Center (151), 1055 Clermont St, Denver, CO 80220. E-mail DrazninB{at}Den-res.org\\ © 2000 American Heart Association, Inc.
Abstract—Pathogenesis
of macrovascular complications of diabetes may involve an activation of
the transcription factor nuclear factor-
B (NF-B) by hyperglycemia
and advanced glycosylation end products (AGEs). Activation of NF-B
is believed to be dependent on activation of the Rho family of GTPases.
Although the precise mechanism of the Rho-mediated action is not
completely understood, posttranslational modification of the Rho
proteins by geranylgeranylation is required for their subsequent
activation. We observed that in cultured vascular smooth muscle cells
(VSMCs), insulin stimulated the activity of geranylgeranyltransferase
(GGTase) I and increased the amounts of geranylgeranylated Rho-A from
47% to 60% (P<0.05). GGTI-286, an inhibitor of
GGTase I, blocked both effects of insulin. Increased availability of
prenylated Rho-A significantly augmented the abilities of angiotensin
II (Ang II), hyperglycemia, and AGEs to activate NF-B, as measured
by NF-B response-element luciferase reporter activity.
Preincubations of VSMCs with insulin for 24 hours doubled NF-B
transactivation by Ang II, hyperglycemia, and AGEs. This priming effect
of insulin was completely inhibited by GGTI-286. We demonstrate for the
first time, to our knowledge, that insulin potentiates
NF-B–dependent transcriptional activity induced by hyperglycemia,
AGEs, and Ang II in VSMCs by increasing the activity of GGTase I and
the availability of geranylgeranylated Rho-A.
Key Words: hyperinsulinemia • muscle, smooth, vascular • angiotensin II • nuclear factor-B • hyperglycemia
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