A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart

J Clin Invest. 2007 Oct;117(10):2812-24. doi: 10.1172/JCI30804.

Abstract

Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v), which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development. Integrated cDNA expression analysis of failing human myocardia uncovered a novel protein kinase, cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v. Expression levels of cardiac-MLCK were well correlated with the pulmonary arterial pressure of patients with heart failure. In cultured cardiomyocytes, knockdown of cardiac-MLCK by specific siRNAs decreased MLC2v phosphorylation and impaired epinephrine-induced activation of sarcomere reassembly. To further clarify the physiologic roles of cardiac-MLCK in vivo, we cloned the zebrafish ortholog z-cardiac-MLCK. Knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides resulted in dilated cardiac ventricles and immature sarcomere structures. These results suggest a significant role for cardiac-MLCK in cardiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Cardiac Myosins / metabolism
  • Cardiac Output, Low / enzymology*
  • Cardiac Output, Low / genetics
  • Cardiac Output, Low / pathology
  • Cells, Cultured
  • Cloning, Molecular
  • Embryo, Nonmammalian / metabolism
  • Female
  • Heart / embryology*
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Myocardium / enzymology
  • Myocardium / ultrastructure*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / ultrastructure
  • Myosin Light Chains / metabolism
  • Myosin-Light-Chain Kinase / antagonists & inhibitors
  • Myosin-Light-Chain Kinase / genetics
  • Myosin-Light-Chain Kinase / metabolism*
  • Myosin-Light-Chain Kinase / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Oligoribonucleotides, Antisense / pharmacology
  • Organogenesis* / genetics
  • Rats
  • Sarcomeres / metabolism*
  • Up-Regulation
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / antagonists & inhibitors
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / physiology*

Substances

  • Myosin Light Chains
  • Oligoribonucleotides, Antisense
  • Zebrafish Proteins
  • myosin light chain 2
  • Myosin-Light-Chain Kinase
  • cardiac myosin light chain kinase, human
  • mylk3 protein, zebrafish
  • Cardiac Myosins