Dipeptidyl Peptidase-4 Modulates Left Ventricular Dysfunction in Chronic Heart Failure via Angiogenesis-Dependent and -Independent Actions

• Published in: Circulation (New York, N.Y.) N.Y.), 2012-10, Vol.126 (15), p.1838-1851
• Main Authors: SHIGETA, Toshimasa, AOYAMA, Morihiko, MUROHARA, Toyoaki, BANDO, Yasuko K, MONJI, Akio, MITSUI, Toko, TAKATSU, Miwa, CHENG, Xiang-Wu, OKUMURA, Takahiro, HIRASHIKI, Akihiro, NAGATA, Kohzo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Chronic Disease; Diabetes Complications - metabolism; Diabetes Complications - physiopathology; Diastole; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - metabolism; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Heart Failure - metabolism; Heart Failure - physiopathology; Humans; Male; Medical sciences; Miscellaneous; Neovascularization, Pathologic - physiopathology; Pharmacology. Drug treatments; Rats; Rats, Inbred Strains; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - physiopathology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.112.096479

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. 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. 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.