Inhibitor κB Kinase 2 is a Myosin Light Chain Kinase in Vascular Smooth Muscle
Rationale: Myosin light chain (MLC) phosphorylation determines vascular contractile status. In addition to the classic Ca2+-dependent MLC kinase (MLCK), another unidentified kinase(s) also contributes to MLC phosphorylation in living cells. Inhibitor κB kinase 2 (IKK2) deficient mouse embryonic fibroblasts (MEFs) demonstrate abnormal morphology and migration, suggesting that IKK2 may be involved in MLC phosphorylation.
Objective: Therefore, we tested if IKK2 is a MLCK in living cells and the role of IKK2 in mediating vasoconstriction and blood pressure regulation.
Methods and Results: In the present study, we showed that recombinant IKK2 phosphorylated MLC and intact myosin in vitro, and the kinetic parameters were comparable to those of the classic MLCK. Over-expression of IKK2 increased cellular MLC phosphorylation level, and pharmacological inhibition of IKK2 markedly decreased vascular smooth muscle cell (VSMC) MLC phosphorylation, suggesting that IKK2 is a MLCK in living cells. IKK2 inhibitors dose- and time-dependently attenuated vasoconstriction elicited by diverse agonists, suggesting the physiological importance of IKK2 as a MLCK. VSMC-specific IKK2 deficient mice had decreased aortic contractile responses, and reduced hypertensive responses to several vasoconstrictors, compared to wild-type mice, confirming the physiological importance of IKK2 as a MLCK.
Conclusions:Our data provide a novel mechanism whereby IKK2 regulates MLC phosphorylation as a MLCK and thus vascular function and blood pressure.
- myosin light chain (MLC)
- vascular smooth muscle
- blood vessels
- blood pressure
- Received April 4, 2013.
- Revision received May 30, 2013.
- Accepted July 1, 2013.