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 −1 ·day −1 ) for 4 weeks. The left ventricles were assessed for cardiac function, fibrosis, mast cells and macrophage phenotype. Mouse cardiac fibroblast and bone marrow‐derived macrophage cultures were exposed to high glucose and treated with GR73632 to assess collagen release, signalling pathways and cytokine release respectively. Proteomics analysis was conducted to assess the left ventricular 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 by high glucose treated mouse cardiac fibroblasts. NK‐1R activation decreased P65 phosphorylation (NF‐ κ B) 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 and macrophages. This study provides a potential target for treatment of diabetic cardiomyopathy.