Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension

Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, China.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 05/2011; 301(2):H584-91. DOI: 10.1152/ajpheart.01212.2010
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Vascular tone, an important determinant of systemic vascular resistance and thus blood pressure, is affected by vascular smooth muscle (VSM) contraction. Key signaling pathways for VSM contraction converge on phosphorylation of the regulatory light chain (RLC) of smooth muscle myosin. This phosphorylation is mediated by Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) but Ca(2+)-independent kinases may also contribute, particularly in sustained contractions. Signaling through MLCK has been indirectly implicated in maintenance of basal blood pressure, whereas signaling through RhoA has been implicated in salt-induced hypertension. In this report, we analyzed mice with smooth muscle-specific knockout of MLCK. Mesenteric artery segments isolated from smooth muscle-specific MLCK knockout mice (MLCK(SMKO)) had a significantly reduced contractile response to KCl and vasoconstrictors. The kinase knockout also markedly reduced RLC phosphorylation and developed force. We suggest that MLCK and its phosphorylation of RLC are required for tonic VSM contraction. MLCK(SMKO) mice exhibit significantly lower basal blood pressure and weaker responses to vasopressors. The elevated blood pressure in salt-induced hypertension is reduced below normotensive levels after MLCK attenuation. These results suggest that MLCK is necessary for both physiological and pathological blood pressure. MLCK(SMKO) mice may be a useful model of vascular failure and hypotension.

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Available from: Weiqi He, Mar 10, 2014
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    • "mice ( He et al . , 2008 ) and SMA - Cre transgenic mice were maintained at the animal center of the Model Animal Research Center of Nanjing University . MLCK SMKO mice ( Mylk flox / flox ; SMA - Cre ) were produced by crossing Mylk flox / flox mice with SMA - Cre transgenic mice . The genotyping strategy used is described in our previous report ( He et al . , 2011a , b ) . All animal procedures were performed according to the guidelines of the"
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    • "were correlated with an increase in RLC phosphorylation (Barron et al. 1979), and RLC phosphorylation is reversed upon relaxation (Barron et al. 1980). Today, further insight into the role of MLCK in different muscle tissues has been provided by the study of animal models with tissue-specific ablation of MLCK (He et al. 2011; Stull et al. 2011; Ding et al. 2010; Zhang et al. 2010). Phosphorylation of RLC plays a modulatory role in striated muscle, because regulation of striated muscle contraction occurs on the thin filament by Ca 2? binding to troponin C (TnC). "
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