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Ca²⁺-calmodulin-dependent protein kinase II-dependent activation of contractility in ferret aorta

Inkyeom Kim *, Hyun-Dong Je *, Cynthia Gallant *, Qian Zhan *, Dee Van Riper †, John A. Badwey *, Harold A. Singer † and Kathleen G. Morgan *‡

1. The present study was undertaken to determine whether Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) participates in the regulation of vascular smooth muscle contraction, and if so, to investigate the nature of the downstream effectors.

2. The contractility of isolated ferret aorta was measured while inhibiting CaMKII either with antisense oligodeoxynucleotides against CaMKII or with the CaMKII inhibitor KN93.

3. Treatment with antisense oligodeoxynucleotides against CaMKII resulted in, on average, a decrease in protein levels of CaMKII to 56 % of control levels and significantly decreased the magnitude of the contraction in response to 51 mM potassium physiological saline solution (KCl). Contraction in response to the phorbol ester DPBA was not significantly affected.

4. The CaMKII blocker KN93 also resulted in a significant decrease in the force induced by 51 mM KCl but caused no significant change in the contraction in response to DPBA or the -adrenoceptor agonist phenylephrine.

5. During contraction with 51 mM KCl, both CaMKII and mitogen-activated protein kinase (MAPK) activity increased, as determined by phospho-specific antibodies. The MAPK phosphorylation level was inhibited by KN93, PD098059 (a MAPK kinase (MEK) inhibitor) and calcium depletion.

6. Myosin light chain (LC20) phosphorylation also increased during contraction with KCl and the increase was significantly blocked by PD098059 as well as by both KN93 and antisense oligodeoxynucleotides to CaMKII.

7. The data indicate that CaMKII plays a significant role in the regulation of smooth muscle contraction and suggest that CaMKII activates a pathway by which MAPK activation leads to phosphorylation of LC20 via activation of myosin light chain kinase.

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