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

Abstract

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.

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…96 97 In particular, MMP-9 has been implicated in inflammatory senescence signature. 98 Pathological remodeling of the ECM can be also regulated by novel factors important in vascular disease, such as Fibulin-5. FBLN5 mediates cell-ECM interactions and elastic fiber assembly and is critical for ECM remodeling.…”

Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling

“…[45] MMP-9 stimulation increased the expression of the pro-inflammatory M1 gene Ccl5, but also decreased the expression of M1 markers Ccl3, interleukin (IL)-1β, and IL-6. Transforming growth factor (TGF)β1, an anti-inflammatory M2 marker, was also down-regulated after MMP-9 treatment.…”

“…The advantage of blood monocytes is that these cells will infiltrate into the LV post-MI, whereas peritoneal macrophages may not fully recapitulate the MI macrophage phenotype. [45, 72] Cells stimulated with interleukin (IL)-1β or lipopolysaccharide (LPS) + interferon (IFN)-γ serve as positive controls for M1 polarization, while IL-4 or IL-10 serve as positive controls for M2 polarization. Other positive controls are macrophages isolated from the infarct region or bone marrow derived macrophages, to compare back how well the in vitro setting recapitulates the in vivo situation.…”

Tissue Inhibitor of Metalloproteinase-1: Actions beyond Matrix Metalloproteinase Inhibition

“…MMP-9, one of the most studied MMPs, is involved in cardiac aging and multiple cardiovascular diseases such as MI, atherosclerosis, and hypertension [1,15]. During cardiac aging, circulating and cardiac MMP-9 increase, and MMP-9 deletion abolishes age-induced diastolic dysfunction, which may be mediated by facilitating anti-inflammatory M2 macrophage polarization and inhibiting collagen deposition [15,16].…”

“…During cardiac aging, circulating and cardiac MMP-9 increase, and MMP-9 deletion abolishes age-induced diastolic dysfunction, which may be mediated by facilitating anti-inflammatory M2 macrophage polarization and inhibiting collagen deposition [15,16]. MMP-9 expression substantially increases post-MI, and MMP-9 deletion attenuates cardiac dilation and dysfunction in both young (8–10 weeks) and aged (11–36 months) mice, indicating detrimental roles of MMP-9 [17,18].…”