Neurokinin-1 Receptor Activation Protects Against Cardiac Fibrosis, Inflammation, and Diastolic Dysfunction in Type 2 Diabetic Mice

Background and Purpose: The pathogenesis of type 2 diabetes mellitus (T2DM)-induced cardiomyopathy involves cardiac fibrosis that leads to diastolic dysfunction. We established that replacement of lost substance P (SP) that occurs in T2DM reduces cardiac fibrosis and decreases inflammation in T2DM mice and non-human primates. This study aimed to identify the specific anti-fibrotic SP receptor. Experimental Approach: Age-matched male wild type (WT) and Lepr db/db mice at 12 weeks of age were treated with either saline or the neurokinin 1 receptor (NK-1R) agonist, GR73632 (300 μg/kg/day) for 4 weeks. The hearts were assessed for cardiac function, fibrosis, mast cells and macrophage phenotype. Mouse cardiac fibroblast cultures were treated with high glucose and GR73632 to assess collagen release and signaling pathways. Proteomics analysis was conducted to assess the cardiac proteomic profile between WT and Lepr db/db mice, and the effects of GR73632. Key Results: NK-1R activation decreased cardiac fibrosis, improved diastolic function, decreased mast cell numbers and promoted an anti-inflammatory macrophage phenotype in Lepr db/db mice. NK-1R activation reduced collagen I production in high glucose treated mouse cardiac fibroblasts. NK-1R activation increased Smad7, whilst decreasing P65 phosphorylation (NF-κB) and CCL2 chemokine release. Proteomic analysis revealed a distinct proteome profile between WT and Lepr db/db mouse hearts. Conclusion and Implications: The NK-1R is the anti-fibrotic SP receptor and improves diastolic function in the diabetic heart. This likely involves direct effects on cardiac fibroblasts. This study provides a potential target for treatment of diabetic cardiomyopathy.