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

16 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 2018

Fingerprint

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, 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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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.",
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