Defining a new metabolic pathway in myocardial disease

Project: CSA

Investigators

  • Mark Edward Anderson (CoI)
  • Gerald W Hart (CoI)

Description

Excessive modification of proteins by O-GlcNAcylation (OGN) is a fundamental event in glucose toxicity, in general, and in diabetic cardiomyopathy, in particular. O-GlcNAc cycling on proteins is controlled by two evolutionarily conserved enzymes. OGN is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA), both of which are specifically targeted to thousands of substrates by a large number of accessory proteins. Although reversing excessive OGN is a clear therapeutic goal in diabetes, OGT itself is not druggable. Constitutive loss of OGT is embryonically lethal and targeted OGT deletion in adult heart causes cardiomyopathy. Thus, a major scientific goal is to understand upstream modulators of OGN signaling that could be targets for new therapeutics. In particular, many studies have shown that excessive OGN contributes directly to diabetic cardiomyopathy. In diabetic heart, CAMKII is abnormally O-GlcNAcylated causing it to become constitutively active contributing to cardiac arrhythmias. Our convincing collaborative preliminary studies, show that activation of CAMKII increases OGN in the heart by directly phosphorylating OGT. Our findings indicate this interplay between CAMKII and OGT creates a feed forward pathological circuit that amplifies myocardial toxicity under conditions of hyperglycemic stress. Earlier studies by the Anderson group identified CaMKII as a central mechanism for mitochondrial calcium entry in myocardial cell death in pathophysiological stress. Hart's group has recently described a direct molecular link between hyperglycemia in diabetes and the dysfunction of cardiac mitochondria. Our preliminary results show that mice with myocardial CaMKII inhibition are protected from excessive OGN in response to pathological stress, while mice with myocardial CaMKII over-expression have markedly increased OGN at baseline. Our new preliminary data suggest CaMKII directly activates OGT to increase OGN and CaMKII inhibition reduces OGN during disease stress. This finding may be highly significant because it will allow control over pathological OGN by targeting CaMKII related pathways upstream to OGT and OGN. The proposed research plan is focused on the relationship between CaMKII and O-GlcNAcylation in diabetic heart disease.
Award amount$750,000.00
Award date07/01/2017
Program typeCollaborative Sciences Award
Award ID17CSA33610107
Effective start/end date07/01/201706/30/2020
StatusFinished