Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice

Ying Ann Chiao, Trevi A. Ramirez, Rogelio Zamilpa, S. Michelle Okoronkwo, Qiuxia Dai, Jianhua Zhang, Yu Fang Jin, Merry L Lindsey

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

AimsAge-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.Methods and resultsWe compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.ConclusionMMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.

Original languageEnglish (US)
Pages (from-to)444-455
Number of pages12
JournalCardiovascular Research
Volume96
Issue number3
DOIs
StatePublished - Dec 1 2012

Fingerprint

Matrix Metalloproteinase 9
Fibrosis
Matrix Metalloproteinase 8
Heart Ventricles
Connective Tissue Growth Factor
Extracellular Matrix
Transforming Growth Factors
Collagen
Smad Proteins
Messenger RNA

Keywords

  • Ageing
  • Collagen
  • Diastolic function
  • Extracellular matrix
  • Matrix metalloproteinase

ASJC Scopus subject areas

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

Cite this

Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. / Chiao, Ying Ann; Ramirez, Trevi A.; Zamilpa, Rogelio; Okoronkwo, S. Michelle; Dai, Qiuxia; Zhang, Jianhua; Jin, Yu Fang; Lindsey, Merry L.

In: Cardiovascular Research, Vol. 96, No. 3, 01.12.2012, p. 444-455.

Research output: Contribution to journalArticle

Chiao, Ying Ann ; Ramirez, Trevi A. ; Zamilpa, Rogelio ; Okoronkwo, S. Michelle ; Dai, Qiuxia ; Zhang, Jianhua ; Jin, Yu Fang ; Lindsey, Merry L. / Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. In: Cardiovascular Research. 2012 ; Vol. 96, No. 3. pp. 444-455.
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AU - Chiao, Ying Ann

AU - Ramirez, Trevi A.

AU - Zamilpa, Rogelio

AU - Okoronkwo, S. Michelle

AU - Dai, Qiuxia

AU - Zhang, Jianhua

AU - Jin, Yu Fang

AU - Lindsey, Merry L

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N2 - AimsAge-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.Methods and resultsWe compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.ConclusionMMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.

AB - AimsAge-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.Methods and resultsWe compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.ConclusionMMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.

KW - Ageing

KW - Collagen

KW - Diastolic function

KW - Extracellular matrix

KW - Matrix metalloproteinase

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