The role of matrix metalloproteinases induced angiogenesis during transition from compensatory cardiac hypertrophy to cardiac failure : therapeutic effects of hydrogen sulfide.
Background: Although matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) play a vital role in tumor angiogenesis and TIMP-3 causes apoptosis, their role in cardiac angiogenesis is unknown. Interestingly, a disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure, however, the proteolytic and anti-angiogenic mechanisms of transition from compensatory hypertrophy to decompensatory heart failure are unclear. Previous studies have shown the cardio protective role of hydrogen sulfide (H2S) in myocardial ischemia, infarction and heart failure, but its role during transition from compensatory cardiac hypertrophy to heart failure is yet to be unveiled. We hypothesize that in pathological pressure overload of the heart, cardiac matrix remodeling is induced by an increase in angiogenic growth factors during the compensatory hypertrophy phase and an increase in antiangiogenic factors during the decompensatory heart failure phase. H2S mitigates the transition from compensatory hypertrophy to decompensatory heart failure by increasing angiogenesis and decreasing fibrosis. Methods: In the first set of experiments, we have created ascending aortic banding (AB) in the mice to mimic pressure overload on the heart and studied the ventricular remodeling events associated with chronic pressure overload. Male wild type mice were used and all animal procedures were performed in accordance with National Institute of Health guidelines for animal research and were reviewed and approved by the Institute Animal Care and use Committee of University of Louisville. Sham animals underwent similar procedures except for aortic banding. Animals were studied at 3 weeks (compensatory phase) and 8 weeks period (decompensatory phase) and compared with sham groups. In the second set of experiment, similar protocol was followed, and animals were treated with hydrogen sulfide (H2S) for 6 weeks by giving sodium hydrosulfide (NaHS) in drinking water and compared with untreated groups. Molecular and functional data were assessed by echocardiography, pressure-volume (P-V) study, immunohistochemistry, histology, western blot, and x-ray angiography. Results: We found that in the first set of experiments, expression of MMP-2 increased along with angiogenic growth factor, vascular endothelial growth factor (VEGF) during compensatory phase (AB 3 weeks group). Expression of MMP-9, TIMP-3 and anti-angiogenic factors, angiostatin, and endostatin increased during decompensatory phase (AB 8 weeks group). There was increased deposition of fibrosis during the decompensatory phase. Sy treating with H2S, we noticed that there was increased expression of VEGF and MMP-2 in AS 8 weeks group than in untreated AS 8 weeks group. Interestingly, the expression of MMP-9,
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The role of matrix metalloproteinases induced angiogenesis during transition from compensatory cardiac hypertrophy to cardiac failure : therapeutic effects of hydrogen sulfide.
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