The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure: Contractility in Health and DiseaseReview Series

Ozgur Ogut, Frank V. Brozovich

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Clinical syndrome of heart failure Regulation of smooth muscle contractility Ca2+ sensitization Ca2+ desensitization MYPT1 isoforms and the sensitivity to cGMP cGMP and MYPT1 phosphorylation Vascular function and cGMP signalling Captopril therapy and MYPT1 Expression in HF Captopril therapy and gene expression Conclusions Abstract The clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP-dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an ∼38-kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3' exon generates MYPT1 isoforms, which differ by a COOH-terminus leucine zipper (LZ). Further, PKGI-mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP-mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP-mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.

Original languageEnglish (US)
Pages (from-to)2158-2164
Number of pages7
JournalJournal of Cellular and Molecular Medicine
Volume12
Issue number6A
DOIs
StatePublished - Dec 2008

Fingerprint

Myosin-Light-Chain Phosphatase
Myocardial Contraction
Leucine Zippers
Mitogen-Activated Protein Kinases
Blood Vessels
Heart Failure
Vasodilation
Smooth Muscle
Protein Isoforms
Muscle Relaxation
Captopril
Health
Cyclic GMP-Dependent Protein Kinase Type I
Nitric Oxide
Holoenzymes
Guanylate Cyclase
Alternative Splicing
Peptidyl-Dipeptidase A
Myosins
Vasoconstriction

Keywords

  • Angiotensin
  • MYPT1
  • Nitric oxide
  • Smooth muscle
  • Vasoconstriction
  • Vasodilatation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

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title = "The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure: Contractility in Health and DiseaseReview Series",
abstract = "Clinical syndrome of heart failure Regulation of smooth muscle contractility Ca2+ sensitization Ca2+ desensitization MYPT1 isoforms and the sensitivity to cGMP cGMP and MYPT1 phosphorylation Vascular function and cGMP signalling Captopril therapy and MYPT1 Expression in HF Captopril therapy and gene expression Conclusions Abstract The clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP-dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an ∼38-kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3' exon generates MYPT1 isoforms, which differ by a COOH-terminus leucine zipper (LZ). Further, PKGI-mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP-mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP-mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.",
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