TY - JOUR
T1 - Hyperinsulinemia enhances transcriptional activity of nuclear factor-κB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells
AU - Golovchenko, Inga
AU - Goalstone, Marc L.
AU - Watson, Peter
AU - Brownlee, Michael
AU - Draznin, Boris
PY - 2000/10/27
Y1 - 2000/10/27
N2 - Pathogenesis of macrovascular complications of diabetes may involve an activation of the transcription factor nuclear factor-κB (NF-κB) by hyperglycemia and advanced glycosylation end products (AGEs). Activation of NF-κB 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-κB, as measured by NF-κB response-element luciferase reporter activity. Preincubations of VSMCs with insulin for 24 hours doubled NF-κB 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-κB-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.
AB - Pathogenesis of macrovascular complications of diabetes may involve an activation of the transcription factor nuclear factor-κB (NF-κB) by hyperglycemia and advanced glycosylation end products (AGEs). Activation of NF-κB 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-κB, as measured by NF-κB response-element luciferase reporter activity. Preincubations of VSMCs with insulin for 24 hours doubled NF-κB 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-κB-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.
KW - Angiotensin II
KW - Hyperglycemia
KW - Hyperinsulinemia
KW - Muscle, smooth, vascular
KW - Nuclear factor-κB
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U2 - 10.1161/01.RES.87.9.746
DO - 10.1161/01.RES.87.9.746
M3 - Article
C2 - 11055977
AN - SCOPUS:0034721925
SN - 0009-7330
VL - 87
SP - 746
EP - 752
JO - Circulation research
JF - Circulation research
IS - 9
ER -