Protein nitrosylation in the antihypertensive mechanisms of treatment with sodium nitrite

• Grant number: 15/22228-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2015
• End date: January 31, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Jose Eduardo Tanus dos Santos
• Grantee: Lucas Cezar Pinheiro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/23946-0 - Sodium nitrite and nitrate: from mechanisms to antihypertensive therapy, AP.TEM

Abstract

In contrast to what it was usually believed in the last decades, many studies carried out in the last years have shown that the anions nitrate and nitrite are not simply inert biological products of nitric oxide (NO) oxidation. In fact, nitrates are secreted by salivary glands into saliva after their absortion in the gastrointestinal system, and nitrates are reduced to nitrites by oral bacteria. Nitrites are converted into NO in the stomach. These transformations correspond to the entero-salivary cycle of nitrates and nitrites, which promote NO formation to supplement the canonical, enzymatic NO formation pathways (NO synthases). While a variety of cardiovascular effects of these ions have been shown, the mechanisms explaining their bioactivation are still poorly understood. Recent studies by our group have shown that the acid conditions of the stomach play a major role in the anti-hypertensive effects of sodium nitrite, even though the mechanisms explaining those effects are not clear. An interesting possibility that has not been explored yet is that the oral administration of sodium nitrite causes the formation of NO-related species, particularly NO+, NO2 e N2O, which can generate nitrosothiols (RSNO) and potentially lead to nitros(yl)ation of proteins (enzymes) and receptors involved in hypertension, thus lowering blood pressure. This projects aims at identifying mechanisms activated by treatment with sodium nitrite or nitrate in animal models of hypertension, cell culture approaches, and nitrosoproteomics thus offering an interdisciplinary and translational perspective. Therefore, this project aims at contributing to the knowledge regarding the following particular issues: 1) to determine the mechanisms involved in the chronic antihypertensive effects of sodium nitrite in rats, particularly the involvement of nitrosothiols (RSNO); 2) to determine whether the formation of RSNO promotes the nitro(sy)lation and inhibition of tissue renin-angiotensin system affecting cell signaling; 3) to determined whether therapy with sodium nitrite or nitrate attenuates the erectile dysfunction associated with hypertension; 4) to determined whether sodium nitrite prevents the vascular remodeling associated with hypertension, possibly as a result of matrix metalloproteinase 2 (MMP-2) inhibition; 5) to determine whether sodium nitrite reverses mitochondrial dysfunction in the vessels and heart from hypertensive animals; 6) to start studies aiming to determine which proteins are nitrosilated in the vessels and heart from animals treated with sodium nitrite by using nitrosoproteomic approaches and validate these findings. (AU)