Regulation of myosin light chain kinase expression by angiotensin II in hypertension.
BACKGROUND
Increased growth and contraction of vascular smooth muscle cells (VSMCs) are major abnormalities in many vascular disorders. To investigate the signaling pathways that mediate these processes, we studied the expression of smooth muscle myosin light chain kinase (smMLCK) in VSMCs.


METHODS
Primary cultured VSMCs isolated from normotensive Wistar-Kyoto (WKY) rats were treated with angiotensin II (Ang II). smMLCK expression was examined in the cells using western blot analysis. In vivo, a specific inhibitor of smMLCK or MAP kinase kinase (MEK) was delivered to spontaneously hypertensive rats (SHRs) using an osmotic pump, and their blood pressures were measured using tail-cuff sphygmomanometry.


RESULTS
Expression of smMLCK protein is rapidly increased by Ang II, an important agonist responsible for increased vasoconstriction and vascular remodeling, in concert with increased myosin light chain phosphorylation. Inhibiting Ang II type 1 (AT1) receptor, Ras, or MEK blocked the Ang II-induced increase in smMLCK expression. In vivo, inhibiting MEK decreased smMLCK expression, blood pressure, and vascular thickening in SHRs. Moreover, inhibiting smMLCK activity decreased blood pressure and smooth muscle mass in arteries in SHRs.


CONCLUSIONS
The regulation of smMLCK expression by Ang II via Ras signaling is important in the regulation of vascular remodeling and blood pressure. Targeting this pathway could be an effective strategy for developing novel therapeutics to treat hypertension.
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
Yoo-Jeong
YJ
Han
Wen-Yang
WY
Hu
Mariann
M
Piano
Primal
P
de Lanerolle
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
D001381:Azepines; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; C070571:ML 7; D000804:Angiotensin II; D009219:Myosin-Light-Chain Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins