MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair

Am J Physiol Heart Circ Physiol. 2019 Jun 1;316(6):H1281-H1296. doi: 10.1152/ajpheart.00532.2017. Epub 2019 Mar 22.


MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts, and MK5 haplodeficiency attenuates the increase in collagen 1-α1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5+/- and wild-type littermate (MK5+/+) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5+/+ and MK5+/- mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5+/+ and LADL-MK5+/- mice. Area at risk did not differ between LADL-MK5+/+ and LADL-MK5+/- hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5+/- hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5+/- hearts compared with LADL-MK5+/+. Although inflammatory cell infiltration was similar in LADL-MK5+/+ and LADL-MK5+/- hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5+/- mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5-/- mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI. NEW & NOTEWORTHY MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.

Keywords: MAP kinase-activated protein kinase-5/p38-regulated/activated protein kinase; extracellular signal-regulated kinase 3/4; fibroblast; myocardial infarction; reparative fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Cicatrix / enzymology*
  • Cicatrix / pathology
  • Cicatrix / physiopathology
  • Collagen / metabolism*
  • Disease Models, Animal
  • Haploinsufficiency*
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Myofibroblasts / enzymology*
  • Myofibroblasts / pathology
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Signal Transduction
  • Ventricular Function, Left
  • Ventricular Remodeling
  • Wound Healing*


  • Intracellular Signaling Peptides and Proteins
  • MAP-kinase-activated kinase 5
  • Collagen
  • Protein-Serine-Threonine Kinases
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse