Document Detail

Dipeptidylpeptidase-4 Modulates Left-Ventricular Dysfunction in Chronic Heart Failure via Angiogenesis-Dependent and -Independent Actions.
MedLine Citation:
PMID:  23035207     Owner:  NLM     Status:  Publisher    
BACKGROUND: The inhibition of dipeptidylpeptidase-4 (DPP4) protects the heart from acute myocardial ischemia. However, the role of DPP4 in chronic heart failure independent of coronary artery disease remains unclear. METHODS AND RESULTS: We first localized the membrane-bound form of DPP4 (m-DPP4) to the capillary endothelia of rat and human heart tissue. Diabetes promoted m-DPP4 activation, leading to reduced myocardial stromal cell-derived factor-1αSDF-1α concentrations and resultant angiogenic impairment in rats. The diabetic rats exhibited diastolic left ventricular dysfunction (DHF) with enhanced interstitial fibrosis partly due to the increased matrix metalloproteinase 2 (MMP2)/tissue inhibitor of metalloproteinases 2 (TIMP2) ratios in a DPP4-dependent fashion. Both genetic and pharmacological DPP4 suppression reversed the SDF-1α-dependent microvasculopathy and DHF associated with diabetes. Pressure overload induced DHF which was reversed by DPP4 inhibition via a GLP-1/cyclic AMP-dependent distinct mechanism from that for diabetic heart. In patients with DHF, the circulating DPP4 (s-DPP4) activity in peripheral veins (PV) was associated with that in coronary sinus (CS) and with E/e', an echocardiographic parameter representing DHF. Comorbid diabetes increased the s-DPP4 activities both in PV and CS. CONCLUSIONS: DPP4 inhibition reverses DHF via m-DPP4/SDF-1α-dependent local actions on angiogenesis and s-DPP4/GLP-1-mediated inotropic actions. Myocardium-derived DPP4 activity in CS can be monitored using PV sampling which partly correlates with DHF index; thus, s-DPP4 may potentially serve as a biomarker for monitoring DHF.
Toshimasa Shigeta; Morihiko Aoyama; Yasuko K Bando; Akio Monji; Toko Mitsui; Miwa Takatsu; Xiang-Wu Cheng; Takahiro Okumura; Akihiro Hirashiki; Kohzo Nagata; Toyoaki Murohara
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-3
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Nagoya University Graduate School of Medicine, Nagoya, Japan;
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