(Verbatim from the application): The long-term objective of this application is to demonstrate that diabetic cardiomyopathy is characterized by myocyte death in which the local renin-angiotensin system (RAS) plays a primary critical role. Hyperglycemia induced by streptozotocin administration is anticipated to activate the transcription factor p53, respectively, by glycosylation and phosphorylation of the C-terminal of this protein. Enhanced p53 function may upregulate p53-dependent genes, such as bax, angiotensinogen and AT1 receptor, leading to the synthesis and secretion of Ang II and the sustained phosphorylation of the tumor suppressor. This vicious cycle may promote the chronic generation of Aug II and an increased susceptibility of cells to die. The induction of bax and the downregulation of bcl-2 by p53 may potentiate not only apoptosis, but also myocyte necrosis, resulting in restructuring of the ventricular wall, chamber dilation and impaired cardiac hemodynainics. Importantly, Aug Il-mediated responses may involve the formation of reactive oxygen species (ROS). ROS may constitute the ultimate signal in the activation of the cell death pathways. Insulin-like growth factor-i (IGF-1) opposes the consequences of p53 by phosphorylating its N-terminal and by stimulating transcription of mdm2 that may lead to the interaction of Mdzn2 and p53 proteins. Mdm2-p53 complexes attenuate p53 function, Ang II concentration, ROS generation, increase in Bax, decrease in Bcl-2 and, ultimately, cell death and ventricular remodeling. These hypotheses will be tested by performing studies in normal mice and transgenic mice overexpressing IGF-1 following the imposition of diabetes. In vivo studies will be complemented with in vitro experiments utilizing myocyte cultures infected with adenoviral vectors overexpressing human mutated p53 or human wild-type p53. These cells will be exposed to high concentration of glucose to establish a cause and effect relationship between triggers of cell death, i.e., glucose and Aug II, and factors preventing, i.e., mutated p53, and promoting, i.e., wild type p53, cell death mechanisms. These multiple analyses should allow to establish whether the myocyte RAS is fundamentally implicated in the development and progression of diabetic cardiomyopathy.
Showing the most recent 10 out of 51 publications
