Regulation of Myosin Light Chain Kinase Expression by Angiotensin II in Hypertension

• Published in: American journal of hypertension 2008-08, Vol.21 (8), p.860-865
• Main Authors: Han, Yoo-Jeong, Hu, Wen-Yang, Piano, Mariann, de Lanerolle, Primal
• Format: Article
• Language: English
• Subjects: Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; Aorta - cytology; Arterial hypertension. Arterial hypotension; Azepines - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Blood Pressure - physiology; Cardiology. Vascular system; Cells, Cultured; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Enzyme Inhibitors - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Hypertension - drug therapy; Hypertension - metabolism; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - enzymology; Myosin-Light-Chain Kinase - antagonists & inhibitors; Myosin-Light-Chain Kinase - metabolism; Naphthalenes - pharmacology; ras Proteins - metabolism; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1 - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Vasoconstrictor Agents - metabolism; Vasoconstrictor Agents - pharmacology
• ISSN: 0895-7061; 1941-7225; 1879-1905
• DOI: 10.1038/ajh.2008.199

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.