AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation.
BACKGROUND
AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs).


RESULTS
Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H2O2 suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activation was Ang II type 1 receptor dependent. Whereas 3H-thymidine incorporation by VSMCs treated with Ang II was significantly inhibited when the cells were pretreated with 1 mmol/L AICAR, the inhibition of AMPK by dominant-negative AMPK overexpression augmented Ang II-induced cell proliferation. Subcutaneous injection of AICAR (1 mg/g body weight per day) for 2 weeks suppressed neointimal formation after transluminal mechanical injury of the rat femoral artery.


CONCLUSIONS
Our findings indicate that Ang II-induced AMPK activation is synchronized with extracellular signal-regulated kinase signaling and that AMPK works as an inhibitor of the Ang II proliferative pathway. AMPK signaling might serve as a new therapeutic target of vascular remodeling in cardiovascular diseases.
Nagata
Daisuke
D
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Takeda
Ryo
R
Sata
Masataka
M
Satonaka
Hiroshi
H
Suzuki
Etsu
E
Nagano
Tetsuo
T
Hirata
Yasunobu
Y
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002455:Cell Division; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction
D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D012265:Ribonucleotides; D000804:Angiotensin II; D000620:Aminoimidazole Carboxamide; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide