Substance P Metabolites and Receptors in the Pathogenesis of Cardiac Disease in Type 1 Diabetes - Cardiovascular disease is the leading cause of death in patients with type 1 diabetes (T1D). A key cardiovascular outcome is left ventricular remodeling in the form of concentric hypertrophy, fibrosis, and vascular remodeling. This results in diastolic dysfunction and eventual heart failure. There are no specific therapies for this adverse remodeling in T1D, therefore, progress in the prevention or regression of this condition requires identification of new treatment approaches. In T1D and T2D there is a loss of the 11 amino acid sensory nerve neuropeptide substance P (SP). Using an animal model of T2D, we identified that replacement of lost SP provides protection against cardiac fibrosis and cardiac dysfunction via activation of the neurokinin 1 receptor (NK-1R). We have subsequently determined that many C-terminal metabolites of SP retain biological activity at the NK-1R, and further determined that a mimetic of the SP metabolite SP7-11, which activates the NK-1R, prevents cardiac fibrosis and restores normal cardiac function in T2D mice. Thus, SP and SP metabolites that activate the NK-1R are cardioprotective in diabetes. Further, we have identified that the N-terminal SP metabolite SP1-9, does not activate the NK-1R but instead is active at the Mas-related G protein-coupled receptor X2 (MrgprX2). This is significant because MrgprX2 is found almost exclusively on mast cells and mast cells contribute to adverse cardiac remodeling, particularly fibrosis. Thus, SP1-9 and MrgprX2 would be predicted to promote adverse cardiac remodeling. Therefore, the current project will utilize fixed and frozen cardiac tissue, plasma, and fixed and frozen coronary vessel tissue to assess SP metabolites, SP receptors, SP metabolizing enzymes, mast cells, fibrosis, as well as available clinical parameters to determine the extent to which cardioprotective and adverse cardiac remodeling-promoting molecules and cells are present in the T1D heart. These parameters will be compared with T2D and non-diabetic hearts. We will also correlate: 1) the assessed parameters with fibrosis/vascular remodeling as primary outcomes; 2) the assessed parameters with each other as secondary outcomes; and 3) the assessed parameters with available clinical data as tertiary outcomes. Emphasis will be placed on the association between SP and SP metabolites with the aforementioned outcomes. Our overall hypothesis is that T1D results in low SP levels, cardiac and coronary vascular remodeling and reduced cardiac function from either decreased neuronal SP production and less NK-1R activation or SP metabolism giving high SP1-9 levels and activation of MrgprX2. We will test our hypothesis using three specific aims: 1) Determine SP, SP metabolites and neuronal SP content in the T1D heart and plasma; 2) Determine SP metabolizing peptidases, NK-1R, MrgprX2, MCs, fibrosis and vascular remodeling in the T1D heart; and 3) Determine the relationship between SP metabolizing peptidases, NK-1R, MrgprX2 and MCs to fibrosis and vascular remodeling in the T1D heart. These studies will provide new insights into the role of SP and SP metabolites in the human heart in T1D and may indicate a new therapeutic approach for cardiac remodeling in T1D patients.
