Journal
CARDIOVASCULAR RESEARCH
Volume 106, Issue 3, Pages 421-431Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvv128
Keywords
Cardiac ageing; Inflammation; Macrophage polarization; MMP-9; Proteomics
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Funding
- American Heart Association Scientist Development Grant [15SDG22930009]
- National Institutes of Health [HHSN 268201000036C (N01-HV-00244), HL075360, P01HL051971, P20GM104357]
- Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award [5I01BX000505]
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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.
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