Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells.
The angiotensin II (AngII) type 1 receptor (AT(1)) plays a critical role in hypertrophy of vascular smooth muscle cells (VSMCs). Although it is well known that G(q) is the major G protein activated by the AT(1) receptor, the requirement of G(q) for AngII-induced VSMC hypertrophy remains unclear. By using cultured VSMCs, this study examined the requirement of G(q) for the epidermal growth factor receptor (EGFR) pathway, the Rho-kinase (ROCK) pathway, and subsequent hypertrophy. AngII-induced intracellular Ca(2+) elevation was completely inhibited by a pharmacological G(q) inhibitor as well as by adenovirus encoding a G(q) inhibitory minigene. AngII (100nm)-induced EGFR transactivation was almost completely inhibited by these inhibitors, whereas these inhibitors only partially inhibited AngII (100nm)-induced phosphorylation of a ROCK substrate, myosin phosphatase target subunit-1. Stimulation of VSMCs with AngII resulted in an increase of cellular protein and cell volume but not in cell number. The G(q) inhibitors completely blocked these hypertrophic responses, whereas a G protein-independent AT(1) agonist did not stimulate these hypertrophic responses. In conclusion, G(q) appears to play a major role in the EGFR pathway, leading to vascular hypertrophy induced by AngII. Vascular G(q) seems to be a critical target of intervention against cardiovascular diseases associated with the enhanced renin-angiotensin system.
Ohtsu
Haruhiko
H
Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
Higuchi
Sadaharu
S
Shirai
Heigoro
H
Eguchi
Kunie
K
Suzuki
Hiroyuki
H
Hinoki
Akinari
A
Brailoiu
Eugen
E
Eckhart
Andrea D
AD
Frank
Gerald D
GD
Eguchi
Satoru
S
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D049108:Cell Enlargement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006984:Hypertrophy; D015151:Immunoblotting; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism
D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000242:Cyclic AMP; D066246:ErbB Receptors; D054460:rho-Associated Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium