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DPPIV inhibition ameliorates cardiorenal function in heart failure rats

Grant number: 12/05821-0
Support type:Scholarships in Brazil - Master
Effective date (Start): July 01, 2012
Effective date (End): June 30, 2014
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Daniel Francisco de Arruda Junior
Home 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

Studies recently published by our research group and by other laboratories have provided convincing evidence that increases in the expression of the major sodium transporters, located in the apical membrane of the renal tubule, play an important role in the sodium and water retention contributing to edema formation in heart failure. These studies emphasize and confirm that the appropriated treatment to contain the progression of cardiovascular diseases requires a cardiorenal approach, considering that little modifications of renal function are strictly associated with cardiovascular morbidity and mortality.The renin-angiotensin system plays a central role in the pathophysiology of HF. Angiotensin II is a powerful vasoconstrictor and an important mediator of sodium and water retention in the proximal tubule, and the main mechanism by which this occurs is by stimulation of the Na+/H+ exchanger isoform 3 (NHE3). In addition, angiotensin II potentiates the neural liberation of catecholamines, is arrhythmogenic, promotes vascular hyperplasia and pathological myocardial hypertrophy, as well as stimulates cardiomyocytes apoptosis. Consequently, angiotensin II antagonists constitute one of the basis for HF treatment. The inhibition of dipeptidyl peptidase IV (DPPIV), the enzyme responsible for the degradation of incretin hormone glucagon-like peptide 1 (GLP-1), represents an effective and safe therapy for patients with type 2 diabetes mellitus. However, due to the myriad of physiological actions of its substrates, the effect of DPPIV inhibition extends further beyond its glycemic benefits. In this context, it has been shown that the GLP-1 and its analogues have cardioprotective effects including reduction of the infarct size and an improvement in the coronary flow, suggesting that DPPIV inhibitors can also be effective for the treatment of HF and acute myocardial infarction. This incretin hormone also exerts renoprotective actions characterized by increments of natriuresis in humans and in experimental models, at least in part, due to inhibition of NHE3 transport activity in the apical membrane of the renal proximal tubule. In light of the above, this project will be undertaken to test the hypothesis that the association between a DPPIV inhibitor and an antagonist of the angiostensin AT1 receptor promotes synergistic cardioprotective and renoprotective actions in animals subjected to myocardial damage. The results obtained from this project may provide the scientific basis for implementation of a novel therapeutic strategy for the treatment of HF.