Angiotensin II and IGF-1 regulate connexin43 expression via ERK and p38 signaling pathways in vascular smooth muscle cells of coronary artery bypass conduits.
BACKGROUND
Changes in connexin expression have been found in vascular smooth muscle cells (VSMCs) during the progression of atherosclerotic lesion and intimal hyperplasia. It is our hypothesis that increased connexin43 expression following stimulation of VSMCs with Ang II and IGF-1 contributes to more proliferation in saphenous vein (SV) than in the internal mammary artery (IMA).


METHODS
Using immunohistochemistry, Western blot, and reverse-transcription polymerase chain reaction, we assessed the effect of Ang II and IGF-1 stimulation on connexin43 expression and the signaling pathways involved in VSMCs of SV and IMA.


RESULTS
Immunostaining demonstrated strong expression of connexin43 in SV compared with IMA after stimulation with Ang II and IGF-1. Ang II up-regulated the expression of connexin43 in VSMCs of SV in a dose- and time-dependent manner. This was inhibited by p38 and ERK MAP kinase inhibitors, SB203580 and PD98059, respectively. In the VSMCs of IMA, the connexin43 expression was markedly low and maintained at a reduced level even after 3 h stimulation. IGF-1 dose-dependently induced mRNA expression of connexin43 in the VSMCs of SV, which was blocked by PD98059. However, in VSMCs of IMA there was no significant effect of IGF-1 on the connexin43 mRNA expression.


CONCLUSIONS
These data suggest that connexin43 expression can be influenced by Ang II and IGF-1 through ERK and p38 pathways and may contribute to the pathogenesis of vein graft disease following coronary artery bypass grafting.
Jia
Guanghong
G
Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Mitra
Amit K
AK
Cheng
Gang
G
Gangahar
Deepak M
DM
Agrawal
Devendra K
DK
D000368:Aged; D000804:Angiotensin II / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018031:Connexin 43; D004791:Enzyme Inhibitors; D005419:Flavonoids; C500216:GJA1 protein, human; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one