• Inflammatory Disease
• Diabetes Mellitus

Dipeptidyl peptidase-4 (DPP-4) is a serine exoprotease that is expressed on the surface of many cells. DPP-4 truncates bioactive molecules, including incretin and nonincretin substrates. Among the substrates degraded by DPP-4 are stromal cell-derived factor-1 alpha (SDF-1α) and the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Yasuko Bando Kureishi, MD Nagoya University Graduate School of Medicine, Nagoya, Japan, studied the effect of DPP-4 inhibition on chronic myocardial remodeling and dysfunction associated with diabetes.

DPP-4 inhibition has been demonstrated to improve mortality and cardiac function in coronary artery disease. Zaruba et al. [Cell Stem Cell 2009] showed that lack of DPP-4 rescues acute myocardial injury by increasing myocardial SDF-1α levels and subsequent angiogenesis in mice.

Dr. Kureishi explored whether DPP-4 and a decline in myocardial SDF-1α are related to microangiopathy in diabetic cardiomyopathy and whether DPP-4 inhibition reverses the SDF-1α decline. The studies showed that cardiac DPP-4 localizes in the cardiac capillary vessel endothelium and that DPP-4 deficiency reverses the decline in SDF-1α levels in the diabetic heart. His experiments also showed that diabetes is associated with decreased cardiac capillary density and with increased cardiac DPP-4 activity in situ and in vitro. DPP-4 deficiency was shown to reverse the decreased capillary density induced by diabetes. Lack of DPP-4 activity also reversed impaired diastolic function in diabetic rodents, with significantly decreased left ventricular diastolic stiffness and minimum rate of ventricular pressure change (dp/dt_min). Dr. Kureishi also found a correlation between circulating DPP-4 activity in the human heart and the early transmitral flow velocity/early diastolic mitral valve annulus velocity ratio in patients with heart failure with preserved ejection fraction.

Dr. Kureishi concluded that cardiac DPP-4 promotes SDF-1α degradation, thereby impairing coronary angiogenesis, which contributes to the cardiac remodeling and diastolic dysfunction associated with diabetes.

• © 2012 MD Conference Express®