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Posttranscriptional and posttranslational regulation of the enzyme dypeptidil peptidase IV in heart failure

Grant number: 14/17135-9
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2015
Effective date (End): May 31, 2019
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Daniel Francisco de Arruda Junior
Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Recent data from our laboratory support the notion that the enzyme dipeptidyl peptidase IV (DPPIV) plays an important role in the pathophysiology of heart failure (HF). DPPIV is a serine protease that cleaves and inactivates a variety of peptides that exert cardioprotective effects, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 alpha (SDF-1±). DPPIV is expressed on the surface of epithelial cells, endothelial cells, fibroblasts and lymphocytes and also in a soluble form in plasma and other body fluids. We have recently demonstrated that DPPIV activity and abundance are increased in the plasma of patients and rats with HF and that the activity of this enzyme is associated with poorer cardiac function and increased pulmonary congestion. Furthermore, activity and expression of DPPIV are elevated in heart endothelial cells of rats with HF. Consistent with these observations, we have also demonstrated that treatment with DPPIV inhibitors are able not only to prevent but also reverse cardiac structural and functional changes in rats with HF. The stimulus and mechanism that lead to increases in the activity and expression of circulating and cardiac endothelial DPPIV in HF have not been established. The source of plasma DPPIV has been attributed to its cleavage from the membrane of the peripheral lymphocytes, especially T lymphocytes, through the catalytic action of an unknown "sheddase". Recent studies have demonstrated that cell surface DPPIV may be upregulated in the kidneys of mice with diabetic nephropathy due to reduced expression of the microRNA29 family members. In this project, we intend to investigate the regulation of circulating and endothelial DPPIV in HF at both posttranscriptional (via family MicroRNAs 29) and posttranslational levels (cleavage of DPPIV from the T-cell membrane to the extracellular compartment). More specifically, we will test the hypotheses that: 1) Increased levels of plasma DPPIV in HF patients and rats is due to decreased expression of this enzyme in T lymphocytes and 2) There is a possible relationship between increased heart DPPIV activity and expression with decreased expression of microRNAs family 29 in this organ and with the progression of cardiac dysfunction in rats with myocardial injury-induced HF.

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Scientific publications
(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)
FONTES, MILENE T.; ARRUDA-JUNIOR, DANIEL F.; DOS SANTOS, DANUBIA SILVA; RIBEIRO-SILVA, JOAO CARLOS; ANTO, EDINEI L.; TUCCI, PAULO F. J.; ROSSONI, LUCIANA V.; GIRARDI, ADRIANA C. C.. Dipeptidyl peptidase 4 inhibition rescues PKA-eNOS signaling and suppresses aortic hypercontractility in male rats with heart failure. Life Sciences, v. 323, p. 10-pg., . (14/17135-9, 16/08907-3, 14/20303-0, 18/05431-3, 16/22140-7, 13/10619-8)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ARRUDA JUNIOR, Daniel Francisco de. Combinated effect of vildagliptin and valsartan on the treatment of heart failure in rats. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.

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