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cGMP effects on vascular tone: modulating the activity of myosin light chain phosphatase

Background

During flow-mediated vasodilatation, nitric oxide activates guanylate cyclase and the resultant increase cGMP leads to an activation of PKGI. PKGI activates a number of targets in the smooth muscle cell that result in smooth muscle relaxation, including MLC phosphatase. MLC phosphatase isolated from smooth muscle is a holoenzyme consisting of three subunits; a 20 kDa subunit, a 38 kDa catalytic subunit and a myosin targeting subunit (MYPT1). MYPT1 has two isoforms that differ by the presence of a an alternatively spliced 31 bp 3' exon; exon inclusion codes for a MYPT1 that lacks a COOH-terminus leucine zipper (LZ-), while exon exclusion shifts the reading frame and codes for a LZ+ MYPT1 isoform.

Results

We have demonstrated that PKGI mediated activation of the MLC phosphatase requires the expression of a LZ+ MYPT1, and the relative expression of LZ+/LZ- MYPT1 isoforms determines the sensitivity to cGMP mediated smooth muscle relaxation. We have also demonstrated that in animal models of heart failure (CHF), LZ+ MYPT1 expression and the sensitivity to cGMP mediated smooth muscle relaxation both decline. Further, activation of p42/44 MAPK, but not p38 MAPK, signaling occurs during CHF, and treatment with angiotensin receptor antagonists prevents the activation of p42/44 MAPK and preserves both normal LZ+ MYPT1 expression and normal sensitivity to cGMP mediated smooth muscle relaxation.

Conclusion

These results suggest that an AT1 receptor mediated activation of the p42/44 MAPK signaling pathway could regulate alternative splicing of the LZ MYPT1 transcript to produce LZ+/LZ- MYPT1 isoforms. Further, a number of investigators have demonstrated that a decrease in LZ+ MYPT1 expression is associated with heart failure, portal hypertension and pre-eclampsia, and thus, LZ MYPT1 expression could be a marker for vascular disease.

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Correspondence to Frank V Brozovich.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Brozovich, F.V. cGMP effects on vascular tone: modulating the activity of myosin light chain phosphatase. BMC Pharmacol 9, S7 (2009). https://doi.org/10.1186/1471-2210-9-S1-S7

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Keywords

  • Nitric Oxide
  • Portal Hypertension
  • Myosin Light Chain
  • Guanylate Cyclase
  • Smooth Muscle Relaxation