Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing after myocardial infarction

Cesar A. Meschiari, Mira Jung, Rugmani Padmanabhan Iyer, Andriy Yabluchanskiy, Hiroe Toba, Michael R. Garrett, Merry L Lindsey

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after myocardial infarction (MI). Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages show better outcomes post-MI, whereas aged TG mice show a worse aging phenotype, we wanted to evaluate the effect of aging superimposed on MI to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17- to 28-mo-old male and female C57BL/6J wild-type (WT) and TG mice (n < 10–21 mice/group) to evaluate the effects of aging superimposed on MI. Despite similar infarct areas and mortality rates at day 7 post-MI, aging TG mice showed improved diastolic properties and remodeling index compared with WT mice (both P < 0.05). Macrophage numbers were higher in TG than WT mice at days 0 and 7 post-MI, and the post-MI increase was due to elevated cluster of differentiation 18 protein levels (all P < 0.05). RNA sequencing analysis of cardiac macrophages isolated from day 7 post-MI infarcts identified 1,276 statistically different (all P < 0.05) genes (994 increased and 282 decreased in TG mice). Reduced expression of vascular endothelial growth factor A, platelet-derived growth factor subunit A, and transforming growth factor-α3, along with elevated expression of tissue inhibitor of MMP-4, in macrophages revealed mechanisms of indirect downstream effects on fibroblasts and neovascularization. While collagen accumulation was enhanced in TG mice compared with WT mice at days 0 and 7 post-MI (P < 0.05 for both), the post-MI collagen cross-linking ratio was higher in WT mice (P < 0.05), consistent with increased diastolic volumes. Vessel numbers [by Griffonia (Bandeiraea) simplicifolia lectin I staining] were decreased in TG mice compared with WT mice at days 0 and 7 post-MI (P < 0.05 for both). In conclusion, macrophage-derived MMP-9 improved post-MI cardiac wound healing through direct and indirect mechanisms to improve diastolic physiology and remodeling. NEW & NOTEWORTHY Aging mice with macrophage overexpression of matrix metalloproteinase-9 have increased macrophage numbers 7 days after myocardial infarction, resulting in improved diastolic physiology and left ventricular remodeling through effects on cardiac wound healing.

Original languageEnglish (US)
Pages (from-to)H224-H235
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume314
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

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Matrix Metalloproteinase 9
Wound Healing
Macrophages
Myocardial Infarction
Transgenic Mice
Collagen
RNA Sequence Analysis
Ventricular Remodeling
Platelet-Derived Growth Factor
Transforming Growth Factors
Vascular Endothelial Growth Factor A
Myocardium

Keywords

  • Angiogenesis
  • Cardiac wound healing
  • Collagen
  • Left ventricular physiology
  • RNA sequencing

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing after myocardial infarction. / Meschiari, Cesar A.; Jung, Mira; Iyer, Rugmani Padmanabhan; Yabluchanskiy, Andriy; Toba, Hiroe; Garrett, Michael R.; Lindsey, Merry L.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 314, No. 2, 01.02.2018, p. H224-H235.

Research output: Contribution to journalArticle

Meschiari, Cesar A. ; Jung, Mira ; Iyer, Rugmani Padmanabhan ; Yabluchanskiy, Andriy ; Toba, Hiroe ; Garrett, Michael R. ; Lindsey, Merry L. / Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing after myocardial infarction. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 314, No. 2. pp. H224-H235.
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