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Role Of MMP9 In Cardiac Stem Cell Differentiation And Autophagy
Author(s) -
Mishra Paras Kumar,
Metreveli Naira,
Chavali Vishalakshi,
Tyagi Neetu,
Qipshidze Natia,
Sen Utpal,
Joshua Irving G.,
Tyagi Suresh C.
Publication year - 2012
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.26.1_supplement.1060.10
Subject(s) - autophagy , myocardial fibrosis , masson's trichrome stain , western blot , mmp9 , immunocytochemistry , fibrosis , cardiac fibrosis , microbiology and biotechnology , chemistry , blot , endocrinology , biology , downregulation and upregulation , medicine , apoptosis , biochemistry , gene
To test the hypothesis that ablation of MMP9 induces cardiac stem cell (CSC) differentiation into cardiomyocytes and inhibits autophagy, we created double knock out (DKO: Ins2+/−/MMP9−/−) mice. The levels of CSC, cardiomyomyocytes and autophagy were determined in the heart of C57BL/6J (WT), Ins2+/− (diabetic) and DKO mice by RT‐PCR, immunocytochemistry, confocal microscopy and Western blotting using c‐kit, troponin and LC3 markers, respectively. The ECM turn over (fibrosis) was measured by Masson Trichrome staining. The cross talk between c‐kit and MMP9 was determined by co‐immunoprecipitation (co‐IP). Interestingly, the degree of fibrosis was correlated with the levels of LC3 and troponin in the WT, Ins2+/− and DKO (mean ± SE: fibrosis −14± 2.1, 34±2.5, 6±1.9; LC3−36±1.5; 39± 0.6, 38±1.0; and troponin−11.2± 0.4, 8.8±0.3, 12.3± 0.28, respectively). Western blot and co‐IP results revealed that induction of MMP9 attenuates c‐kit in the diabetic heart. Based on these findings, it is suggested that robust expression of MMP9 exacerbates autophagy and alleviates cardiomyocytes in diabetes. Our results elicit a novel mechanism, where abrogation of MMP9 promotes differentiation of CSC into cardiomyocytes and improves their survival by inhibiting autophagy.