Early growth response gene-1 expression in vascular smooth muscle cells effects of insulin and oxidant stress.
BACKGROUND
Cardiovascular mortality is increased in individuals with insulin resistance, and increased oxidant stress is strongly implicated in atherogenesis. Early growth response gene-1 (Egr-1) may be an important link between insulin resistance and oxidant stress. In this study we examined the effects of insulin and oxidant stress on Egr-1 expression in vascular smooth muscle cells (VSMC), and identified mechanisms for these effects on Egr-1.


METHODS
Rat VSMC were used to obtain time course and dose-response curves for insulin and oxidant stress on Egr-1 protein expression. Intracellular signaling pathway inhibitors and adenoviral vectors with dominant negative effects on specific signaling pathways were used to determine mechanisms for these effects.


RESULTS
Insulin and oxidant stress each significantly stimulate Egr-1 protein expression. Insulin and oxidant stress combined have a greater effect on Egr-1 than either alone. Insulin effects are mediated via the ERK1/2 MAP kinase pathway, whereas oxidant stress effects may be mediated via the ERK5 and p38 MAP kinase pathways.


CONCLUSIONS
We demonstrated that insulin and oxidant stress stimulate Egr-1 expression in VSMC. Insulin effects are mediated via the ERK1/2 MAP kinase pathway, whereas oxidant stress effects may be mediated via the ERK5 and p38 MAP kinase pathways. As insulin resistance is characterized by compensatory hyperinsulinemia and selective impairment of the PI 3-kinase pathway with intact signaling along the ERK1/2 MAP kinase pathway, this may have implications for accelerated atherosclerosis in insulin resistance.
Research Service, Denver Veterans Affairs Medical Center, Denver, Colorado. Wang@UCHSC.edu
Cecilia C Low
CC
Wang
Girish
G
Sharma
Boris
B
Draznin
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D007328:Insulin / Q000494:pharmacology / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D007328:Insulin; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D048051:p38 Mitogen-Activated Protein Kinases