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

Yonggang Ma, Ying Ann Chiao, Ryan Clark, Elizabeth R. Flynn, Andriy Yabluchanskiy, Omid Ghasemi, Fouad Zouein, Merry L. Lindsey, Yu Fang Jin

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)421-431
Number of pages11
JournalCardiovascular research
Volume106
Issue number3
DOIs
StatePublished - Jun 1 2015

Keywords

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

ASJC Scopus subject areas

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

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    Ma, Y., Chiao, Y. A., Clark, R., Flynn, E. R., Yabluchanskiy, A., Ghasemi, O., Zouein, F., Lindsey, M. L., & Jin, Y. F. (2015). Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence. Cardiovascular research, 106(3), 421-431. https://doi.org/10.1093/cvr/cvv128