Premium
DPPI Deficiency Enhances Both Angiogenesis and Arteriogenesis and Improves Cardiac Function after Myocardial Infarction
Author(s) -
Kolpakov Mikhail A,
Hooshdaran Bahman,
Guo Xinji,
Wang Tao,
Rafiq Khadija,
Vlasenko Liudmila,
Qi Zhao,
Garikipati Venkata NS,
Kishore Raj,
Houser Steven R,
Sabri Abdelkarim
Publication year - 2016
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.30.1_supplement.1211.2
Subject(s) - angiogenesis , vascular endothelial growth factor , proteases , matrix metalloproteinase , angiopoietin , vascular endothelial growth factor a , inflammation , chemistry , medicine , endocrinology , biology , enzyme , biochemistry , vegf receptors
Study objective Myocardial infarction (MI) induces both hypoxia and inflammation that trigger angiogenesis. Numerous proangiogenic and proarteriogenic factors are released during the inflammatory reaction post‐MI. However, the overall effect of the various factors of the inflammatory component depends on the local environment. This study examined the potential role of inflammatory serine protease (ISP) inhibition on angiogenesis after MI. Methods and results We subjected wild‐type (WT) and mice lacking Dipeptidyl peptidase I (DPPI), a lysosomal enzyme involved in the cleavage and activation of major ISPs, to MI up to 4 weeks and assessed the role of DPPI gene deletion on angiogenesis and cardiac remodeling and function. DPPI deficient mice show markedly reduced activity of neutrophil‐ and mast cell‐derived serine proteases after MI compared to WT mice, along with a reduction in infarct size and improved cardiac function. DPPI deficiency also increased the number of capillaries and mature vessels in infarcted hearts by upregulating the expression of angiogenic cytokines such as vascular endothelial growth factor (VEGF) and angiopoietin‐1. Investigation of the mechanisms involved show reduced levels of soluble VEGF receptor 1 (sVEGFR1) accumulation in DPPI KO infarct together with increased phosphorylation of VEGFR2. The negative role of inflammatory serine proteases on angiogenesis was further demonstrated in vitro in tube formation assay. Treatment of human umbilical vein endothelial cells with the neutrophil‐derived serine protease cathepsin G (CG) led to up‐regulation of sVEGFR1 and its interaction with VEGFA, decreased VEGFR2 signaling and reduced the number and length of endothelial cell tubes. In contrast, preincubation of endothelial cells with neutralizing anti‐sVEGFR1 antibodies attenuated endothelial cell tube disorganization, improved VEGFR2 signaling and preserved new vessels formation. Conclusions Our findings reveal the role of ISPs as key components of a molecular mechanism that negatively modulates angiogenesis through regulation of the relative levels of sVEGFR1 in endothelial cells. Our study also point to DPPI inhibition as a potential therapeutic target for stimulation of angiogenesis and the maintenance of cardiac function post‐MI. Support or Funding Information This work was supported by the National Institute of Health (HL088626 and HL076799) and American Heart Association (15SDG22650004 and 14PRE20380518).