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Dipeptidyl peptidase IV as a potential target for the therapy of heart failure

Abstract

Heart failure (HF) represents a major public health problem and is a major cause of disability and death in the modern world. The raise in worldwide life expectancy and the fact that HF is the final common pathway for a host of cardiac disorders strongly suggest that the substantial healthcare expenditures and social impact associated with this syndrome will continue to escalate. Such aspects justify the effort to obtain a better understanding of the HF syndrome, particularly with regard to enable the development of novel therapeutic and preventive approaches. Dipeptidyl peptidase IV (DPPIV) is a serine protease that can be found anchored to the plasma cell membrane or in its soluble form in plasma. Its function is to cleave peptide chains in which there is an alanine or proline as the second amino acid from the N-terminus. DPPIV substrates as brain natriuretic peptide (BNP), glucagon like peptide-1 (GLP-1) and stromal cell-derived factor 1 (SDF-1alpha) are of great importance in the cardiovascular system. Recent data from our laboratory have shown that there is an increase in the abundance and activity of DPPIV in plasma and cardiac endothelium of rats with HF, suggesting that this peptidase plays an important role in the pathophysiology of HF. Consistent with this idea, we have found that DPPIV inhibitors exert cardioprotective and renoprotective actions that prevent the development of HF in rats subjected to myocardial injury. However, it is still unknown whether DPPIV inhibition can reverse cardiac dysfunction in rats with established HF. In addition, it remains to be established whether the increased activity of DPPIV is restricted to the cardiac endothelium and whether the higher activity of DPPIV in HF is associated with a greater severity of endothelial dysfunction. Moreover, the stimulus that increases the circulating level and activity of DPPIV in HF remains to be determined. In view of the above, this project will explore the potential therapeutic use of DPPIV inhibitors in HF. More specifically, we will test the hypothesis that DPPIV inhibitors exert therapeutic effects in rats with established HF; that the simultaneous administration of the DPPIV inhibitor vildagliptin and the angiotensin II AT1 receptor antagonist valsartan exerts synergistic action in the treatment of HF; and that increased expression and activity of DPPIV in endothelial cells correlates with the severity of endothelial dysfunction in HF rats, as well as in human saphenous veins obtained from patients undergoing aortocoronary bypass surgery. The regulation of circulating and endothelial DPPIV in HF rats, at both posttranscriptional (via MicroRNA-29 family) and posttranslational levels (through the catalytic action of a yet unidentified "sheddase", that is most likely expressed in T lymphocytes), as well as the possible correlation between regulation of DPPIV activity/expression and progression of cardiac dysfunction will also be addressed in this project. (AU)

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Scientific publications (12)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BERALDO, JULIANA ISA; BENETTI, ACARIS; BORGES-JUNIOR, FLAVIO ARAUJO; ARRUDA-JUNIOR, DANIEL F.; MARTINS, FLAVIA LETICIA; JENSEN, LEONARDO; DARIOLLI, RAFAEL; SHIMIZU, MARIA HELOISA; SEGURO, ANTONIO C.; LUCHI, WEVERTON M.; et al. Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 8, . (16/22140-7, 13/10619-8)
CRAJOINAS, RENATO O.; POLIDORO, JULIANO Z.; CARNEIRO DE MORAIS, CARLA P. A.; CASTELO-BRANCO, REGIANE C.; GIRARDI, ADRIANA C. C.. Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 311, n. 5, p. C768-C776, . (12/10146-0, 13/10619-8)
CARNEIRO DE MORAIS, CARLA P.; POLIDORO, JULIANO Z.; RALPH, DONNA L.; PESSOA, THAISSA D.; OLIVEIRA-SOUZA, MARIA; BARAUNA, VALERIO G.; REBOUCAS, NANCY A.; MALNIC, GERHARD; MCDONOUGH, ALICIA A.; GIRARDI, ADRIANA C. C.. Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, v. 309, n. 8, p. C541-C550, . (13/50384-0, 12/10146-0, 13/10619-8)
ARRUDA-JUNIOR, DANIEL F.; MARTINS, FLAVIA L.; DARIOLLI, RAFAEL; JENSEN, LEONARDO; ANTONIO, EDNEI L.; DOS SANTOS, LEONARDO; TUCCI, PAULO J. F.; GIRARDI, ADRIANA C. C.. Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure. FRONTIERS IN PHYSIOLOGY, v. 7, . (13/10619-8)
ARRUDA-JUNIOR, DANIEL F.; MARTINS, FLAVIA L.; SALLES, THIAGO ALMEIDA; JENSEN, LEONARDO; DARIOLLI, RAFAEL; ANTONIO, EDNEI L.; DOS SANTOS, LEONARDO; CRAJOINAS, RENATO O.; TUCCI, PAULO J. F.; GOWDAK, LUIS HENRIQUE W.; et al. Postprandial increase in glucagon-like peptide-1 is blunted in severe heart failure. Clinical Science, v. 134, n. 9, p. 1081-1094, . (13/10619-8, 13/17368-0, 16/22140-7)
YOSHIZAKI, AMANDA; ANTONIO, EDNEI LUIZ; SILVA JUNIOR, JOSE ANTONIO; CRAJOINAS, RENATO OLIVEIRA; SILVA, FLAVIO ANDRE; COSTA GIRARDI, ADRIANA CASTELLO; BOCALINI, DANILO SALES; PORTES, LESLIE ANDREWS; NEVES DOS SANTOS, LUIS FELIPE; CARLOS, FERNANDO PEREIRA; et al. Swimming Training Improves Myocardial Mechanics, Prevents Fibrosis, and Alters Expression of Ca2+ Handling Proteins in Older Rats. JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, v. 73, n. 4, p. 468-474, . (13/10619-8, 15/11028-9)
SAVIGNANO, FERNANDA A.; CRAJOINAS, RENATO O.; PACHECO, BRUNA P. M.; CAMPOS, LUCIENE C. G.; SHIMIZU, MARIA HELOISA M.; SEGURO, ANTONIO CARLOS; GIRARDI, ADRIANA C. C.. Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature. European Journal of Pharmacology, v. 811, p. 38-47, . (12/10146-0, 13/10619-8)
VIEIRA, STELLA DE SOUZA; ANTONIO, EDNEI LUIZ; DE MELO, BRUNNO LEMES; PORTES, LESLIE ANDREWS; MONTEMOR, JAIRO; OLIVEIRA, HELENITA ANTONIA; MARTINS, FLAVIA LETICIA; ZOGBI, CAMILA; GIRARDI, ADRIANA COSTA; SILVA, JR., JOSE ANTONIO; et al. Exercise Training Potentiates The Cardioprotective Effects of Stem Cells Post-infarction. HEART LUNG AND CIRCULATION, v. 28, n. 2, p. 263-271, . (15/11028-9, 13/10619-8)
SALLES, THIAGO A.; DOS SANTOS, LEONARDO; BARAUNA, VALERIO G.; GIRARDI, ADRIANA C. C.. Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 16, n. 2, p. 4226-4249, . (13/10619-8)
SALLES, THIAGO DE ALMEIDA; ZOGBI, CAMILA; DE LIMA, THAIS MARTINS; CARNEIRO, CAMILA DE GODOI; GARCEZ, ALEXANDRE TELES; BARBEIRO, HERMES VIEIRA; ANTONIO, EDNEI LUIZ; DOS SANTOS, LEONARDO; PEREIRA, ALEXANDRE DA COSTA; FERREIRA TUCCI, PAULO JOSE; et al. The contributions of dipeptidyl peptidase IV to inflammation in heart failure. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 310, n. 11, p. H1760-H1772, . (09/54225-8, 13/10619-8, 11/07402-1)
FARAH, LIVIA X. S.; VALENTINI, VANESSA; PESSOA, THAISSA D.; MALNIC, GERHARD; MCDONOUGH, ALICIA A.; GIRARDI, ADRIANA C. C.. The physiological role of glucagon-like peptide-1 in the regulation of renal function. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 310, n. 2, p. F123-F127, . (12/10146-0, 13/10619-8)
MACHADO BERGER, REBECA CALDEIRA; VASSALLO, PAULA FRIZERA; CRAJOINAS, RENATO DE OLIVEIRA; OLIVEIRA, MARILENE LUZIA; MARTINS, FLAVIA LETICIA; NOGUEIRA, BRENO VALENTIM; MOTTA-SANTOS, DAISY; ARAUJO, ISABELLA BINOTTI; FORECHI, LUDIMILA; COSTA GIRARDI, ADRIANA CASTELLO; et al. Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats. PLoS One, v. 10, n. 10, . (12/10146-0, 13/10619-8)

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