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Enhanced endothelial cell senescence by lithium‐induced matrix metalloproteinase‐1 expression
Author(s) -
Mao Catherine D,
Struewing Ian T,
Barnett Corey D,
Durham Samuel N
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.312.4
Subject(s) - mmp1 , senescence , matrix metalloproteinase , microbiology and biotechnology , inflammation , biology , chemistry , immunology , gene expression , biochemistry , gene
Endothelial cell (EC) senescence and dysfunction occurring after chronic injury and/or inflammation are highly associated with development and progression of cardiovascular diseases. However the factors involved in the establishment of EC senescence remain poorly understood. We have previously shown that lithium, an inhibitor of GSK3β and activator of the Wnt/β‐catenin signaling pathway, was inducing a G2/M cell cycle arrest and a cell‐senescent phenotype in EC. Herein, we show that lithium induces a rapid and pronounced up‐regulation of the matrix metalloproteinase (MMP)1, an inflammation and senescent‐cell marker, at the mRNA and protein levels. In contrast, the up‐regulation of two other senescent‐cell markers is either moderate (IL8) or delayed (PAI1). Moreover, this striking up‐regulation of MMP1 by lithium is specific among other MMPs as the expression of MMP2 and MMP14 are slightly increased and decreased respectively. This lithium effect is independent of GSK3β inhibition as both the expression of the kinase dead‐GSK3β and of GSK3β‐siRNAs fail to increase MMP1 expression while increasing IL8 mRNA expression. Interestingly, the exogenous addition of activated MMP1 is able to increase the number of EC positive for the SA‐β‐galactosidase marker with or without lithium treatment, suggesting that MMP1 participates in the establishment and/or maintenance of the EC‐senescent phenotype. Grant support: HL‐68698.