Neonatal exposure to hyperoxia results in oxidative stress-induced increased MMP-2 activity, SERCA proteolysis and cardiac remodeling and dysfunction

• Grant number: 22/07380-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: May 27, 2023
• End date: November 26, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Michele Mazzaron de Castro
• Grantee: Marcela Maria Blascke de Mello
• Supervisor: Anne Monique Nuyt
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Université de Montréal, Canada
• Associated to the scholarship: 20/02619-1 - Potential effects of matrix metalloproteinase (MMP)-2 on the sarcoplasmic reticulum calcium ATPase (SERCA) in Hypertension-induced vascular dysfunction, BP.DD

Abstract

Prematurity is associated with increased risks of cardiovascular diseases as hypertension in adult life. Angiotensin II contributes to increase the production of reactive oxygen species (ROS) and increase matrix metalloproteinase (MMP)-2 activity. MMP-2 proteolyzes extracellular matrix components and intracellular proteins in vascular smooth muscle cells and heart during hypertension, such as troponin I, calponin-1 and the sarcoplasmic reticulum calcium ATPase (SERCA). SERCA proteolysis in the acute cardiac ischemia-reperfusion injury impairs contractile function. ROS also directly oxidizes SERCA in some cardiovascular diseases, thus impairing its activity. Resveratrol attenuates vascular and cardiac injury caused by ROS in animal models of hypertension and perinatal treatment with resveratrol prevents development of hypertension later in life. Neonatal treatment with resveratrol, concomitantly to hyperoxia exposure (80% of O2), prevents oxidative stress-induced MMP-2 activation, SERCA proteolysis, cardiac remodeling and dysfunction. Sprague-Dawley pups will be keep with their mother in 80% O2 or room air from days 3 to 10 postnatal and treated with Resveratrol or vehicle by gavage from P3-P10. After 10 days or 4 weeks, hearts will be removed to perform DHE in situ, lucigenin chemiluminescence, gelatin zymography, Western blot, RT-qPCR and activity assays for antioxidant enzymes. Cardiac function will be also assessed in 4-week old rats. (AU)