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Am J Physiol Heart Circ Physiol (December 19, 2002). doi:10.1152/ajpheart.00680.2002
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Submitted on August 1, 2002
Accepted on December 10, 2002

Increased Myofibrillar Protein Phosphatase-1 Activity Impairs Rat Aortic Smooth Muscle Activation After Hypoxia

Hwee Teoh1, Mary E. Zacour2, Avraham D. Wener1, Lakshman Gunaratnam1, and Michael E. Ward1*

1 Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
2 Medicine, Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: wardm{at}smh.toronto.on.ca.

We hypothesized that increased myofibrillar type 1 phosphatase (PP1) catalytic activity contributes to impaired aortic smooth muscle contraction after hypoxia. Our results show that inhibition of PP1 activity with microcystin-LR (50 nmol/L) or okadaic acid (100 nmol/L) increased phenylephrine- and KCl-induced contraction to a greater extent in aortic rings from rats exposed to hypoxia (10% O2) for 48 hours than in rings from normoxic animals and restored the level of phosphorylation of the 20 kDa myosin light chain (LC20) during maximal phenylephrine-induced contraction to that observed in the normoxic control group. Myofibrillar PP1 activity was greater in aortas from rats exposed to hypoxia than in normoxic rats (p<0.05). Levels of the targeting protein (MYPT1) that mediates myofibrillar localization of PP1 activity were increased in aortas from hypoxic rats (193[plusmn]28% of the normoxic control value, p<0.05) and in human aortic smooth muscle cells after hypoxic (1% O2) incubation (182[plusmn]18% of the normoxic control value, p<0.05). Aortic levels of myosin light chain kinase were similar in normoxic and hypoxic groups. We conclude that following hypoxia, increased MYPT1 protein expression and myofibrillar PP1 activity impair aortic vasoreactivity through enhanced dephosphorylation of LC20.




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