British journal of pharmacology · 2026
Neurokinin-1 receptor activation protects against cardiac fibrosis, inflammation and diastolic dysfunction in type 2 diabetic mice.
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Widiapradja Alexander, Connery Heather, Helmick Brody J, Schafner Kallie J, Manchikalapudi Vamsi, Horvath Hannah, Gugino Sophia, Kriska Tamas, Herrnreiter Anja, DeVallance Evan, Campbell William B, Levick Scott P
Аннотация
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 Leprdb/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 Leprdb/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 Leprdb/db mice. NK-1R activation reduced collagen I production by high glucose treated mouse cardiac fibroblasts. NK-1R activation decreased P65 phosphorylation (NF-κB) and CCL2 chemokine release. Proteomic analysis revealed a distinct proteome profile between WT and Leprdb/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.
EXPERIMENTAL APPROACH: Age-matched male wild type (WT) and Leprdb/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 Leprdb/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 Leprdb/db mice. NK-1R activation reduced collagen I production by high glucose treated mouse cardiac fibroblasts. NK-1R activation decreased P65 phosphorylation (NF-κB) and CCL2 chemokine release. Proteomic analysis revealed a distinct proteome profile between WT and Leprdb/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.