title: Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions.
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.
  
  
  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.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Shigeta
authors.forename: Morihiko
authors.initials: M
authors.lastname: Aoyama
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.forename: Akio
authors.initials: A
authors.lastname: Monji
authors.forename: Toko
authors.initials: T
authors.lastname: Mitsui
authors.forename: Miwa
authors.initials: M
authors.lastname: Takatsu
authors.forename: Xiang-Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okumura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirashiki
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D002908:Chronic Disease; D048909:Diabetes Complications / Q000378:metabolism* / Q000503:physiopathology; D003971:Diastole; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018819:Dipeptidyl Peptidase 4