Mechanisms involved in cardiac anti-hypertrophic effects of inorganic nitrite in arterial hypertension

• Grant number: 21/01954-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2022
• End date: January 31, 2025
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jose Eduardo Tanus dos Santos
• Grantee: Thaís Ribeiro Vitorino
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Systemic Arterial Hypertension (SAH) is a public health problem that affects 32.5% of the Brazilian population. This disease is often accompanied by left ventricular hypertrophy (LVH), characterized by intense remodeling of the extracellular matrix. Studies demonstrate the participation of extracellular matrix metalloproteinases (MMPs), promoting cardiac remodeling in SAH. MMPs are activated in the presence of oxidative stress, an important pathogenic factor in cardiovascular diseases, especially in SAH. Oxidative stress is also responsible for the lower bioavailability of nitric oxide (NO) since free radicals interact with bioavailable NO generating peroxynitrite (ONOO), which is one of the main species of nitrogen (ERN) MMP-2. The activity of MMPs can be controlled not only by regulating gene expression but also by post-translational mechanisms, such as glutathione and nitrosylation of these proteins. Studies show that the acidic environment of the stomach provides a series of reactions produced that give rise to NO and other nitrosing compounds when sodium nitrite is administered orally. By increasing gastric pH, there is a reduction in the antihypertensive effects caused by oral nitrite. Thus, the hypothesis of this project is that chronic treatment with nitrite decreases cardiac hypertrophy through inhibition of MMP-2 and this may occur due to the antioxidant effects of sodium nitrite and/or by the increase in nitrosylation and/or reduction in protein glutatilation, which are capable of inhibiting MMP-2 activity. To evaluate this hypothesis used Sham and 2K1C animals that will be treated with sodium nitrite at different doses and omeprazole. The animals' blood pressure will be measured weekly by tail plethysmography. Will be determined the plasma rules for nitrite and nitrosothiols. The activity/expression of MMPs will be observed in situ and by electrophoresis using zymography, immunofluorescence, and western blotting. We will also evaluate in vitro whether there is direct inhibition of MMP-2 by sodium nitrite. Hypertrophy will be analyzed through morphological analysis of cardiac tissue, cardiac hypertrophy index, and western blotting for myosin. (AU)