Payne Michael C, Zhang Hai-Ying, Prosdocimo Tony, Joyce Katherine M, Koga Yasuhiko, Ikebe Mitsuo, Fisher Steven A
Department of Medicine, 422 BRB, 2109 Adelbert Road, Case Western Reserve School of Medicine, Cleveland, OH 44106-4958, USA.
J Mol Cell Cardiol. 2006 Feb;40(2):274-82. doi: 10.1016/j.yjmcc.2005.07.009. Epub 2005 Dec 13.
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.
我们正在使用肌球蛋白磷酸酶靶向亚基（MYPT1）作为模型基因来研究平滑肌表型多样性。肌球蛋白磷酸酶（MP）是平滑肌舒张的主要效应器，而MYPT1是调节平滑肌张力信号的关键靶点。在门静脉高压模型中，我们先前已表明门静脉和肠系膜上动脉中MYPT1亚型的表达存在动态变化。我们推测这代表了向肌肉肥大的胎儿表型特征的逆转。在此，我们研究了血管平滑肌表型特化过程中的MP。在出生后第6天至12天之间，门静脉中MYPT1的表达增加了约两倍，MP活性也有类似增加。MYPT1从C末端亮氨酸拉链（LZ）阳性剪接变体亚型转变为LZ阴性亚型。这与从对cGMP介导的血管舒张敏感（10^(-7) M）转变为抗性相一致。这与MYPT1 C末端LZ是MP的cGMP依赖性激活所必需的模型一致。其他收缩蛋白表达的一致变化与从慢张力型到快相收缩型表型的转变相一致。相比之下，主动脉平滑肌在整个发育过程中均表达MYPT1 LZ阳性亚型，并对cGMP舒张。我们提出，新生儿血管平滑肌表型特化过程中的MP亚型转换可能决定了从胎儿循环到成人循环转变过程中血管对NO/cGMP信号的反应变化。
