| Grant number: | 13/10619-8 |
| Support Opportunities: | Regular Research Grants |
| Start date: | October 01, 2014 |
| End date: | September 30, 2016 |
| Field of knowledge: | Biological Sciences - Pharmacology - Cardiorenal Pharmacology |
| Principal Investigator: | Adriana Castello Costa Girardi |
| Grantee: | Adriana Castello Costa Girardi |
| 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 |
| City of the host institution: | São Paulo |
| Associated researchers: | Alexandre da Costa Pereira ; Gerhard Malnic ; Leonardo dos Santos ; Valerio Garrone Barauna |
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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