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

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

Research output: Contribution to journalArticle

104 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)675-688
Number of pages14
JournalCirculation Research
Volume112
Issue number4
DOIs
StatePublished - Feb 15 2013

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Heart Rupture
Macrophage Activation
Matrix Metalloproteinases
Myocardial Infarction
Heart Ventricles
Ventricular Remodeling
Extracellular Matrix
Collagen
Protein-Lysine 6-Oxidase
Myofibroblasts
Tensile Strength
Extracellular Matrix Proteins
Matrix Metalloproteinase 9

Keywords

  • MMP-28
  • fibroblast
  • inflammation
  • macrophage phenotype
  • myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. / Ma, Yonggang; Halade, Ganesh V.; Zhang, Jianhua; Ramirez, Trevi A.; Levin, Daniel; Voorhees, Andrew; Jin, Yu Fang; Han, Hai Chao; Manicone, Anne M.; Lindsey, Merry L.

In: Circulation Research, Vol. 112, No. 4, 15.02.2013, p. 675-688.

Research output: Contribution to journalArticle

Ma, Yonggang ; Halade, Ganesh V. ; Zhang, Jianhua ; Ramirez, Trevi A. ; Levin, Daniel ; Voorhees, Andrew ; Jin, Yu Fang ; Han, Hai Chao ; Manicone, Anne M. ; Lindsey, Merry L. / Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. In: Circulation Research. 2013 ; Vol. 112, No. 4. pp. 675-688.
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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.",
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AU - Ma, Yonggang

AU - Halade, Ganesh V.

AU - Zhang, Jianhua

AU - Ramirez, Trevi A.

AU - Levin, Daniel

AU - Voorhees, Andrew

AU - Jin, Yu Fang

AU - Han, Hai Chao

AU - Manicone, Anne M.

AU - Lindsey, Merry L.

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