Key result
Acute hypoxia downregulates LZ(+) MYPT1 expression by suppressing PKG levels and promotes its interaction with RhoA or ROCK1/ROCK2, thereby promoting pulmonary arterial SMC contraction.
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Acute hypoxia promotes pulmonary arterial smooth muscle cell contraction by downregulating LZ(+) MYPT1 expression via PKG suppression and altering its kinase interactions.
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.
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Singh et al. (2011) studied Hypoxia-induced pulmonary arterial smooth muscle cell contraction. Acute hypoxia vs. Normoxia was evaluated on Expression of LZ(+)MYPT1, interaction with PKG and Rho kinases, and MLC(20) phosphorylation. Acute hypoxia downregulates LZ(+) MYPT1 expression by suppressing PKG levels and promotes its interaction with RhoA or ROCK1/ROCK2, thereby promoting pulmonary arterial SMC contraction.