TY - JOUR
T1 - Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice
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.
N1 - Funding Information:
This work was supported by the Translational Science Training (TST) Across Disciplines program at the University of Texas Health Science Center at San Antonio, with funding provided by the University of Texas System’s Graduate Programs Initiative, to Y.A.C.; NSF 0649172, NIH EB009496, and NIH 1SC2 HL101430 to Y-FJ; and NIH HHSN 268201000036C (N01-HV-00244) for the San Antonio Cardiovascular Proteomics Center and R01 HL-075360, the Max and Minnie Tomerlin Voelcker Fund, and the Veteran’s Administration (Merit) to M.L.L.
PY - 2012/12/1
Y1 - 2012/12/1
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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U2 - 10.1093/cvr/cvs275
DO - 10.1093/cvr/cvs275
M3 - Article
C2 - 22918978
AN - SCOPUS:84869389745
SN - 0008-6363
VL - 96
SP - 444
EP - 455
JO - Cardiovascular research
JF - Cardiovascular research
IS - 3
ER -