Abstract 14409: Cardiac Angiogenesis and Arteriogenesis Suppression After Myocardial Infarction Through Activation of Dipeptidyl Peptidase I
Introduction: Inflammatory cells participation in new blood vessel formation is critical for tissue repair in response to tissue injury, such as myocardial infarction (MI). However, the mechanism(s) underlying this process remain elusive.
Hypotesis: We assessed the role of inflammatory serine proteases (ISPs) by comparing MI-mediated angiogenesis and arteriogenesis in mice lacking dipeptidyl peptidase I (DPPI), a lysosomal enzyme involved in the activation of major ISPs.
Methods and results: DPPI expression and activity were increased early after MI and remained elevated up to 4 weeks post-MI. DPPI deficient mice show markedly reduced activity of neutrophil- (-33%, P<0.05) and mast cell-derived serine proteases (-50%, P<0.05) after MI compared to WT mice, along with a reduction in infarct size (-30%, P<0.05) and improved cardiac contractile function (+30-60%%, P<0.05). 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) A and B. 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 ISPs 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 led to up-regulation of sVEGFR1 and its interaction with VEGFA, decreased VEGFR2-mediated signaling and reduced tube formation ability. In contrast, preincubation of endothelial cells with neutralizing anti-sVEGFR1 antibodies attenuated cathepsin G-induced endothelial cell tube disorganization, improved VEGFR2 signaling and preserved new vessels formation.
Conclusions: Our findings reveal ISPs as key components of a molecular mechanism that negatively modulates angiogenesis through upregulation 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.
Author Disclosures: M.A. Kolpakov: None. B. Hooshdaran: None. X. Guo: None. K. Rafiq: None. L. Vlasenko: None. Y.V. Bashkirova: None. T. Wang: None. Z. Qi: None. V.N. Garikipati: None. R. Kishore: None. A. Sabri: None.
- © 2016 by American Heart Association, Inc.