Abstract
Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 (SDF-α), all of which play important roles in the cardiovascular system. In this regard, recent reports have documented that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental heart failure (HF). Moreover, emerging evidence indicates that DPPIV inhibitors exert cardioprotective and renoprotective actions in a variety of experimental models of cardiac dysfunction. On the other hand, conflicting results have been found when translating these promising findings from preclinical animal models to clinical therapy. In this review, we discuss how DPPIV might be involved in the cardio-renal axis in HF. In addition, the potential role for DPPIV inhibitors in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water.
Highlights
Heart failure (HF) is a complex syndrome characterized by the inability of the heart to pump sufficient amounts of blood to the circulation, or it can only do so by elevating ventricular filling pressures
Dipeptidyl peptidase IV (DPPIV), known as CD26, is a widely expressed serine peptidase that exists on the surface of various cell types; its expression level differs greatly among cells
Des-serine-proline BNP3–32, the cleaved form of brain natriuretic peptide (BNP) yielded by N-terminal dipeptide removal by DPPIV [108], displays remarkably reduced natriuretic actions and a lack of vasodilatory activity compared to BNP1–32 [109]
Summary
Heart failure (HF) is a complex syndrome characterized by the inability of the heart to pump sufficient amounts of blood to the circulation, or it can only do so by elevating ventricular filling pressures. The potential role for gliptins in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water. Emerging evidence from both preclinical and clinical studies raises the possibility that DPPIV might be involved in the pathophysiology of HF. A possible explanation for this unexpected observation arose from a study by Kanasaki and colleagues [46], which demonstrated that linagliptin increases the expression of components of the microRNA (miRNA) 29 family, which in turn reduce DPPIV abundance in the kidneys and endothelial cells of STZ-induced diabetic mice. The protease activity of DPPIV can be beneficial for the cardiovascular system by cleaving neuropeptide Y (NPY) and peptide YY (PYY)
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