Inhibition of the AMP-activated protein kinase-α2 accentuates agonist-induced vascular smooth muscle contraction and high blood pressure in mice.

Content Provider	Semantic Scholar
Author	Wang, Shuangxi Liang, Bin Viollet, Benoit Zou, Ming-Hui
Copyright Year	2011
Abstract	The aim of the present study was to determine the effects and molecular mechanisms by which AMP-activated protein kinase (AMPK) regulates smooth muscle contraction and blood pressure in mice. In cultured human vascular smooth muscle cells, we observed that activation of AMPK by 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside inhibited agonist-induced phosphorylation of myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1). Conversely, AMPK inhibition with pharmacological or genetic means potentiated agonist-induced the phosphorylation of MLC and MYPT1, whereas it inhibited both Ras homolog gene family member A and Rho-associated kinase activity. In addition, AMPK activation or Rho-associated kinase inhibition with Y27632 abolished agonist-induced phosphorylation of MLC and MYPT1. Gene silencing of p190-guanosine triphosphatase-activating protein abolished the effects of AMPK activation on MLC, MYPT1, and Ras homolog gene family member A in human smooth muscle cells. Ex vivo analyses revealed that agonist-induced contractions of the mesenteric artery and aortas were stronger in both AMPKα1(-/-) and AMPKα2(-/-) knockout mice than in wild-type mice. Inhibition of Rho-associated kinase with Y27632 normalized agonist-induced contractions of AMPKα1(-/-) and AMPKα2(-/-) vessels. AMPKα2(-/-) mice had higher blood pressure along with decreased serine phosphorylation of p190-guanosine triphosphatase-activating protein. Finally, inhibition of the Ras homolog gene family member A/Rho-associated kinase pathway with Y27632, which suppressed MYPT1 and MLC phosphorylation, lowered blood pressure in AMPKα2(-/-) mice. In conclusion, AMPK decreases vascular smooth muscle cell contractility by inhibiting p190-GTP-activating protein-dependent Ras homolog gene family member A activation, indicating that AMPK may be a new therapeutic target in lowering high blood pressure.
File Format	PDF HTM / HTML
DOI	10.1161/HYPERTENSIONAHA.110.168906
Alternate Webpage(s)	http://hyper.ahajournals.org/content/hypertensionaha/early/2011/04/04/HYPERTENSIONAHA.110.168906.full.pdf?download=true
Alternate Webpage(s)	http://hyper.ahajournals.org/content/hypertensionaha/early/2011/04/04/HYPERTENSIONAHA.110.168906.full.pdf
Alternate Webpage(s)	http://hyper.ahajournals.org/content/hypertensionaha/57/5/1010.full.pdf?download=true
PubMed reference number	21464390
Alternate Webpage(s)	https://doi.org/10.1161/HYPERTENSIONAHA.110.168906
Journal	Medline
Volume Number	57
Issue Number	5
Journal	Hypertension
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article