Myosin phosphatase isoform switching in vascular smooth muscle development

Department of Medicine, 422 BRB, 2109 Adelbert Road, Case Western Reserve School of Medicine, Cleveland, OH 44106-4958, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 4.66). 03/2006; 40(2):274-82. DOI: 10.1016/j.yjmcc.2005.07.009
Source: PubMed


We are using the myosin phosphatase targeting subunit (MYPT1) as a model gene to study smooth muscle phenotypic diversity. Myosin phosphatase (MP) is the primary effector of smooth muscle relaxation, and MYPT1 is a key target of signals that regulate smooth muscle tone. In a model of portal hypertension we previously showed dynamic changes in the expression of MYPT1 isoforms in the portal vein and upstream mesenteric artery. We hypothesized that this represents a reversion to the fetal phenotype characteristic of muscle hypertrophy. Here we studied MP during vascular smooth muscle phenotypic specification. Between postnatal days 6 and 12 the expression of MYPT1 increased approximately twofold in portal vein with a similar increase in MP activity. MYPT1 switched from C-terminal leucine zipper (LZ) positive to LZ negative splice variant isoforms. This was concordant with a switch from sensitive (10(-7) M) to resistant to cGMP-mediated vascular relaxation. This is consistent with the model in which the MYPT1 C-terminal LZ is required for cGMP-dependent activation of MP. Concordant changes in the expression of other contractile proteins were consistent with a switch from a slow-tonic to a fast-phasic contractile phenotype. In contrast aortic smooth muscle throughout development expressed the MYPT1 LZ positive isoform and relaxed to cGMP. We propose that MP isoform switching during neonatal vascular smooth muscle phenotypic specification may determine changing vascular responses to NO/cGMP signaling in the transition from the fetal to the adult circulation.

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Available from: Michael Payne, Oct 03, 2015
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    • "Moreover, a decreased expression of LZ+ was correlated with congestive heart failure. The leucine-zipper deficient isoform (LZ-) alternatively interacts with PKG1α through its N1-N2 coiled-coil domain but is cGMPinsensitive (Payne et al., 2006). "
    Affinity Chromatography, 03/2012; , ISBN: 978-953-51-0325-7
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    • "The effect of PKG on MLCP requires its binding to the leucine zipper domain in the C-terminal of MYPT1. The expression of the leucine zipper domain in MYPT1 is modulated by various physiological and pathophyiological conditions (Chen et al., 2006; Dou et al., 2010; Payne et al., 2006), which may alter the action of PKG on MLCP. Studies also show that PKG/MYPT1 signaling plays a greater role in mediating relaxation of proximal arteries induced by NO than that of distal arteries in coronary vasculature (Ying et al., 2011). "
    Gao Y · Dou D · Qin X · Qi H · Ying L
    Protein Kinases, Edited by Xavier GDS, 01/2012: chapter 15: pages 337-356; InTech - Open Access Publisher., ISBN: 979-953-307-575-3
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    • "Regulation of expression levels of MYPT1 (+LZ) via the NO–cGMP–PKG pathway plays a key role in smooth muscle relaxation under a number of physiological and pathophysiological conditions.[14] For instance, in rats between postnatal days 6 and 12, expression of MYPT1 in portal veins switches from LZ (+) to LZ (-) isoforms,[11] which is concordant with a switch from cGMP-sensitive vascular relaxation to insensitivity to cGMP.[11212425] In the rat model of congestive heart failure, decreased relaxation of the aorta is associated with decreased expression of MYPT1 (+LZ).[72426] "
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    ABSTRACT: We have shown previously that acute hypoxia downregulates protein kinase G (PKG) expression and activity in ovine fetal pulmonary vessels and pulmonary arterial smooth muscle cells (SMC). Here, we report that acute hypoxia also reduces the expression of leucinezipper-positive MYPT1 (LZ(+)MYPT1), a subunit of myosin light chain (MLC) phosphatase, in ovine fetal pulmonary arterial SMC. We found that in hypoxia, there is greater interaction between LZ(+) MYPT1 and RhoA and Rho kinase 1 (ROCK1)/Rho kinase 2 (ROCK2) and decreased interaction between LZ(+) MYPT1 and PKG, resulting in increased MLC(20) phosphorylation, a higher pMLC(20)/MLC(20) ratio and SMC contraction. In normoxic SMC PKG overexpression, LZ(+) MYPT1 expression is upregulated while PKG knockdown had an opposite effect. LZ(+) MYPT1 overexpression enhanced the interaction between PKG and LZ(+) MYPT1. Overexpression of a mutant LZ(-) MYPT1 isoform in SMC mimicked the effects of acute hypoxia and decreased pMLC(20)/MLC(20) ratio. Collectively, our data suggest that hypoxia downregulates LZ(+) MYPT1 expression by suppressing PKG levels, reduces the interaction of LZ(+) MYPT1 with PKG and promotes LZ(+) MYPT1 interaction with RhoA or ROCK1/ROCK2, thereby promoting pulmonary arterial SMC contraction.
    10/2011; 1(4):487-98. DOI:10.4103/2045-8932.93548
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