Dipeptidyl Peptidase-4 Modulates Left Ventricular Dysfunction in Chronic Heart Failure via Angiogenesis-Dependent and -Independent ActionsClinical Perspective
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.
- diabetes mellitus
- dipeptidyl peptidase 4
- glucagon-like peptide 1
- heart failure
- Received September 25, 2011.
- Accepted August 25, 2012.
- © 2012 American Heart Association, Inc.