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

Abstract

AIMS:

Age-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 RESULTS:

We 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.

CONCLUSION:

MMP-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.

• Authors: Ying Ann Chiao, Trevi A Ramirez, Rogelio Zamilpa, S Michelle Okoronkwo, Qiuxia Dai, Jianhua Zhang, Yu-Fang Jin, Merry L Lindsey
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 96 Issue 3 Pg. 444-55 (Dec 01 2012) ISSN: 1755-3245 [Electronic] England
• PMID: 22918978 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CCN2 protein, mouse
• Cell Adhesion Molecules
• Postn protein, mouse
• Smad2 Protein
• Smad2 protein, mouse
• Transforming Growth Factor beta
• Connective Tissue Growth Factor
• Collagen
• MMP8 protein, mouse
• Matrix Metalloproteinase 8
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Age Factors
• Aging (metabolism, pathology)
• Animals
• Blood Pressure
• Cell Adhesion Molecules (genetics, metabolism)
• Collagen (metabolism)
• Connective Tissue Growth Factor (genetics, metabolism)
• Diastole
• Female
• Fibrosis
• Gene Expression Regulation
• Genotype
• Male
• Matrix Metalloproteinase 8 (genetics, metabolism)
• Matrix Metalloproteinase 9 (deficiency, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (enzymology, pathology)
• Phenotype
• Phosphorylation
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Smad2 Protein (genetics, metabolism)
• Systole
• Transforming Growth Factor beta (genetics, metabolism)
• Ventricular Dysfunction, Left (enzymology, etiology, genetics, pathology, physiopathology, prevention & control)
• Ventricular Function, Left