Mechanism of NF-kB activation in the heart in diabetes

• Grant number: 12/20227-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: January 17, 2013
• End date: January 16, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Dulce Elena Casarini
• Grantee: Larissa Miranda Pereira
• Supervisor: Rajesh Kumar
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Texas A&M University, United States
• Associated to the scholarship: 11/13058-1 - Functional evaluation of angiotensin convertin enzyme (ACE) by site-directed changes, BP.DR

Abstract

Several cellular mechanisms participate in the development of diabetes-induced cardiac dysfunction. A role of the tissue renin-angiotensin system (RAS) in diabetic cardiomyopathy has been demonstrated by clinical and experimental studies. Diabetes is also a disease of chronic inflammation; the latter having deleterious effects on the cardiovascular function. The nuclear factor kB (NF-kB) family of transcription factors is the major mediator of inflammation. NF-kB also controls the expression of angiotensinogen (AGT) gene, the precursor of a bioactive peptide of the RAS, angiotensin II (Ang II). Conversely, Ang II activates NF-kB, thereby generating a positive feedback loop. Similarly, TNF-±, a pro-inflammatory cytokine, activates and is positively regulated by NF-kB. These observations suggest concurrent increase in the expression of both AGT and TNF-± in diabetes. However, our preliminary studies have shown phasic and inverse relationship between AGT and TNF-± expression in hearts of diabetic mice. These observations point to previously unknown mechanisms of NF-kB activation in diabetes that differentially control AGT and TNF-± expression. Our hypothesis is that NF-kB activation undergoes phasic switch between canonical and non-canonical pathways in diabetes. The objective of this study is to determine temporal NF-kB activation mechanisms in diabetic heart and their correlation with AGT and TNF-± expression. The phasic and inverse relationship between AGT and TNF-± suggest that the RAS and inflammation may have more defined roles than previously thought in the etiology of diabetes-induced cardiac dysfunction, understanding of which will significantly benefit the management of diabetic cardiomyopathy. (AU)