Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Circulation. 2012 Oct 9;126(15):1838-51. doi: 10.1161/CIRCULATIONAHA.112.096479. Epub 2012 Oct 3.

Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions.

Author information

  • 1Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Abstract

BACKGROUND:

The inhibition of dipeptidyl peptidase-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 to the capillary endothelia of rat and human heart tissue. Diabetes mellitus promoted the activation of the membrane-bound form of DPP4, leading to reduced myocardial stromal cell-derived factor-1α concentrations and resultant angiogenic impairment in rats. The diabetic rats exhibited diastolic left ventricular dysfunction (DHF) with enhanced interstitial fibrosis caused partly by the increased ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 in a DPP4-dependent fashion. Both genetic and pharmacological DPP4 suppression reversed the stromal cell-derived factor-1α-dependent microvasculopathy and DHF associated with diabetes mellitus. Pressure overload induced DHF, which was reversed by DPP4 inhibition via a glucagon-like peptide-1/cAMP-dependent mechanism distinct from that for diabetic heart. In patients with DHF, the circulating DPP4 activity in peripheral veins was associated with that in coronary sinus and with E/e', an echocardiographic parameter representing DHF. Comorbid diabetes mellitus increased the circulating DPP4 activities in both peripheral veins and coronary sinus.

CONCLUSIONS:

DPP4 inhibition reverses DHF via membrane-bound DPP4/stromal cell-derived factor-1α-dependent local actions on angiogenesis and circulating DPP4/glucagon-like peptide-1-mediated inotropic actions. Myocardium-derived DPP4 activity in coronary sinus can be monitored by peripheral vein sampling, which partly correlates with DHF index; thus, circulating DPP4 may potentially serve as a biomarker for monitoring DHF.

PMID:
23035207
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Write to the Help Desk