Role of histones on cardiac dysfunction in sepsis-induced cardiomyopathy

• Grant number: 19/13751-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): November 01, 2019
• Effective date (End): October 31, 2020
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Cristina Antoniali Silva
• Grantee: Murilo Eduardo Graton
• Supervisor: Francis Joseph Miller
• Host Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Research place: Duke University, United States
• Associated to the scholarship: 17/18436-0 - Study of the post-translational mechanisms involved on increased nitric oxide bioavailability in spotaneoulsy hypertensive rats treated with apocynin, BP.DR

Abstract

Sepsis is a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection. The major cause of morbidity and mortality in sepsis is cardiac dysfunction. During sepsis, histones can be released into the circulation due to extensive inflammation and cellular death. Circulating histone levels are correlated to disease severity and the major mediator of myocardial dysfunction in septic patients. Extracellular histones appear to mediate tissue damage through multiple mechanisms. Histones increase superoxide production and NAD(P)H oxidase (NOX) 1-mediated reactive oxygen species (ROS) generation. Cultured rat cardiomyocytes (H9c2) exposed to calf thymus histones (CTH) showed a concentration-dependent increase in mitochondrial superoxide levels. However, the detailed mechanism of cellular ROS generation following exposure to extracellular histones remains to be uncovered. The goal of this study is to explore potential mechanisms of histone-mediated mitochondrial ROS production in cardiomyocytes and cardiac dysfunction using in vitro and in vivo models of sepsis-induced cardiomyopathy. Cultured cardiomyocytes will be treated with CTH to analyze mitochondrial damage and ROS production. Mice will undergo cecal ligation and puncture to induce sepsis and echocardiographic left ventricle analysis. The obtained data will be expressed as mean ± SEM, and compared between groups. The most appropriate statistical test will be applied to the type of comparison, using specific software. The significance level of p <0.05 will identifystatistically significant differences.