The neuropeptide substance P (SP) induces pro- and anti-fibrotic responses in the heart. Canonically, SP activates the neurokinin 1 receptor (NK1R), encoded by the Tacr1 gene. In the diabetic heart, SP is anti-fibrotic and treatment with the NK1R agonist, GR73632, normalizes fibrosis and cardiac dysfunction. Conversely, in the hypertensive heart, SP is pro-fibrotic. However, whether the NK1R is also anti-fibrotic in the hypertensive heart, or is pro-fibrotic, remains undetermined. We aimed to define the role of the NK1R in a mouse model of hypertension. 8-week-old male wildtype (WT) or Tacr1 -/- mice received saline (n=10 fibrosis was also assessed using picrosirius red staining. Cardiac fibrosis occurred in WT+AngII mice vs WT+Saline (0.7±0.2 vs 0.3±0.1%, p0.9999 vs WT+AngII) and were normalized by GR73632 (3.4±0.1 mg/mm&276.8±15.2 mm 2 , p<0.001 vs WT+AngII). The number of macrophages was increased in WT+AngII mice vs WT+Saline (60±3.5 vs 39.9±5.4 cells/field, p<0.0001) and was further increased in Tacr1 -/- +AngII mice (70±3.9 cells/field, p<0.01 vs WT+AngII). Macrophage number was normalized by GR73632 (36.4±5.8 cells/field vs WT+AngII, p<0.0001). Overall, NK1R-deletion exacerbated fibrosis with sustained diastolic dysfunction. GR73632 prevented fibrosis and diastolic dysfunction. This indicates that the NK1R is protective in the hypertensive heart, and that the pro-fibrotic effects of SP in the hypertensive heart are mediated by another receptor.
Schafner et al. (Fri,) studied this question.