Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation.

Abstract

RATIONALE:

Matrix metalloproteinase (MMP)-28 regulates the inflammatory and extracellular matrix responses in cardiac aging, but the roles of MMP-28 after myocardial infarction (MI) have not been explored.

OBJECTIVE:

To determine the impact of MMP-28 deletion on post-MI remodeling of the left ventricle (LV).

METHODS AND RESULTS:

Adult C57BL/6J wild-type (n=76) and MMP null (MMP-28((-/-)), n=86) mice of both sexes were subjected to permanent coronary artery ligation to create MI. MMP-28 expression decreased post-MI, and its cell source shifted from myocytes to macrophages. MMP-28 deletion increased day 7 mortality because of increased cardiac rupture post-MI. MMP-28(-/-) mice exhibited larger LV volumes, worse LV dysfunction, a worse LV remodeling index, and increased lung edema. Plasma MMP-9 levels were unchanged in the MMP-28((-/-)) mice but increased in wild-type mice at day 7 post-MI. The mRNA levels of inflammatory and extracellular matrix proteins were attenuated in the infarct regions of MMP-28(-/-) mice, indicating reduced inflammatory and extracellular matrix responses. M2 macrophage activation was impaired when MMP-28 was absent. MMP-28 deletion also led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired as a result of decreased expression and activation of lysyl oxidase in the infarcts of MMP-28(-/-) mice. The LV tensile strength at day 3 post-MI, however, was similar between the 2 genotypes.

CONCLUSIONS:

MMP-28 deletion aggravated MI-induced LV dysfunction and rupture as a result of defective inflammatory response and scar formation by suppressing M2 macrophage activation.

• Authors: Yonggang Ma, Ganesh V Halade, Jianhua Zhang, Trevi A Ramirez, Daniel Levin, Andrew Voorhees, Yu-Fang Jin, Hai-Chao Han, Anne M Manicone, Merry L Lindsey
• Journal: Circulation research (Circ Res) Vol. 112 Issue 4 Pg. 675-88 (Feb 15 2013) ISSN: 1524-4571 [Electronic] United States
• PMID: 23261783 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cell Adhesion Molecules
• Cytokines
• Extracellular Matrix Proteins
• Receptors, Cytokine
• Collagen
• Protein-Lysine 6-Oxidase
• Matrix Metalloproteinases, Secreted
• Mmp28 protein, mouse
• Matrix Metalloproteinase 9

Topics

• Animals
• Cell Adhesion Molecules (biosynthesis, genetics)
• Cicatrix (enzymology, etiology)
• Collagen (metabolism)
• Cytokines (biosynthesis, genetics)
• Extracellular Matrix Proteins (biosynthesis, genetics)
• Female
• Gene Expression Regulation
• Heart Rupture (enzymology, etiology)
• Inflammation
• Macrophage Activation (physiology)
• Macrophages (classification, enzymology)
• Male
• Matrix Metalloproteinase 9 (blood)
• Matrix Metalloproteinases, Secreted (deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (blood, complications, enzymology, physiopathology)
• Myocytes, Cardiac (enzymology)
• Myofibroblasts (metabolism)
• Protein-Lysine 6-Oxidase (metabolism)
• Pulmonary Edema (enzymology, etiology)
• Receptors, Cytokine (biosynthesis, genetics)
• Transcription, Genetic
• Ventricular Dysfunction, Left (enzymology, etiology)
• Ventricular Remodeling (genetics, physiology)