Analyses of the functions of MYPT family, novel anchoring proteins, in cardiovascular system by their knockout and transgenic mice

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MYPT is a target subunit of myosin phosphates (MP), in which MYPT interacts with a catalytic subunit (PP 1 cδ) and the other regulatory subunit, M20. MYPT could also interact with other molecules including RhoA and cGMP-dependent protein kinase Iα, indicating that MYPT has a role as an anchoring protein. MYPT1 is a target subunit of smooth muscle/nonmuscle MP and MYPT2 is that of cardiac/skeletal muscle MP. To investigate the in vivo function of MYPTs, we generated MYPT1-deficient mice and MYPT2 transgenic mice, and analyzed these phenotypesThe heterozygous of MYPT1-deficient mice showed no changes in the expression levels of MYPT1 and no phenotypes as compared with those in the wild type mice, however, none of the F2 mice was homozygous for the MYPT1 deletion, indicating that the targeted disruption of the MYPT1 gene results in embryonic lethality. The point of embryonic lethality is considered to be before 7.5 dpc. These findings indicate that MYPT1 is essential for mouse embryogenes … More isThe transgenic mice overexpressing MYPT2 (Tg) using α-MHC promoter demonstrated a significantly increased expression of MYPT2 (>20 folds) specifically in hearts with a concomitant increase of the endogenous PP1cδ. The phosphorylation levels of regulatory myosin light chain (RLC) in Tg were significantly lower than those in the wild type mice (Wt). These results suggest the specific in vivo interaction of MYPT2 with PP1cδ, which could dephosphorylate RLC in heart. Survival rate, body weight, heart rate and blood pressure were not significantly different between Tg and Wt. Heart weight/body weight ratio of Tg was significantly higher than that of Wt. Echocardiography demonstrated the dilation of LU dimension (LVDd and LVDs) and the moderate impairment of LV function in Tg. These results suggest that the overexpression of MYPT2 and the concomitant increased MP activity decreased LV contractility, resulting in mild LV dilatation. Taken together, MP seems to play a role in cardiac function in vivo Less