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

Abstract

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.

• Authors: Sherin Ali Nawaito, Pramod Sahadevan, Marie-Élaine Clavet-Lanthier, Philippe Pouliot, Fatiha Sahmi, Yanfen Shi, Marc-Antoine Gillis, Frederic Lesage, Matthias Gaestel, Martin G Sirois, Angelo Calderone, Jean-Claude Tardif, Bruce G Allen
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 316 Issue 6 Pg. H1281-H1296 (06 01 2019) ISSN: 1522-1539 [Electronic] United States
• PMID: 30901279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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