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Cardiovasc Res. 2015 Jun 1;106(3):421-31. doi: 10.1093/cvr/cvv128. Epub 2015 Apr 15.

Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence.

Author information

1
San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
2
San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Department of Pathology, University of Washington, Seattle, WA, USA.
3
San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Department of Electrical and Computer Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
4
San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA Research Services, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA mllindsey@umc.edu yufang.jin@utsa.edu.
5
San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Department of Electrical and Computer Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA mllindsey@umc.edu yufang.jin@utsa.edu.

Abstract

AIMS:

Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing.

METHODS AND RESULTS:

Young (6-9 months), middle-aged (12-15 months), old (18-24 months), and senescent (26-34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated. Using an identified inflammatory pattern, we were able to define individual mice based on their biological, rather than chronological, age. Bcl6, Ccl24, and Il4 were the strongest inflammatory markers of the cardiac ageing signature. The decline in early-to-late LV filling ratio was most strongly predicted by Bcl6, Il1r1, Ccl24, Crp, and Cxcl13 patterns, whereas LV wall thickness was most predicted by Abcf1, Tollip, Scye1, and Mif patterns. With age, there was a linear increase in cardiac M1 macrophages and a decrease in cardiac M2 macrophages in WT mice; of which, both were prevented by MMP-9 deletion. In vitro, MMP-9 directly activated young macrophage polarization to an M1/M2 mid-transition state.

CONCLUSION:

Our results define the cardiac ageing inflammatory signature and assign MMP-9 roles in mediating the inflammaging profile by indirectly and directly modifying macrophage polarization. Our results explain early mechanisms that stimulate ageing-induced cardiac fibrosis and diastolic dysfunction.

KEYWORDS:

Cardiac ageing; Inflammation; MMP-9; Macrophage polarization; Proteomics

PMID:
25883218
PMCID:
PMC4498140
DOI:
10.1093/cvr/cvv128
[Indexed for MEDLINE]
Free PMC Article

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