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

84 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

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

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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