Key result
In a mouse model of hypertension, the NK1R agonist GR73632 normalized cardiac fibrosis (0.3% vs 0.7%, p<0.0001) and diastolic dysfunction compared to untreated hypertensive controls.
Why the study?
Does NK1R activation with GR73632 or deletion of Tacr1 alter cardiac fibrosis and dysfunction in a mouse model of hypertension?
Does NK1R activation with GR73632 or deletion of Tacr1 alter cardiac fibrosis and dysfunction in a mouse model of hypertension?
Absolute Event Rate: 0.3% vs 0.7%
p-value: p=<0.0001
Activation of the neurokinin 1 receptor protects against adverse cardiac remodeling, fibrosis, and diastolic dysfunction in a hypertensive mouse model.
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&8, respectively) or Angiotensin II (AngII) (1000ng/kg/body weight, n=10 for both groups), a known hypertensive stimuli, for 14 days via subcutaneous osmotic minipumps. An additional group of WT+AngII mice received daily subcutaneous injections of GR73632 (300mg/kg/day, n=9). Left ventricular (LV) function was determined by pressure volume analysis; 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%, p<0.01) and was exacerbated by Tacr1 deletion (1.1±0.4%). Cardiac fibrosis was normalized with GR73632 (0.3±0.1%, p<0.0001 vs WT+AngII). End diastolic pressure was also increased in WT+AngII mice compared to control (3.9±1.1 vs 1.2±0.1 mmHg), remaining unchanged in Tacr1 -/- +AngII mice (1.2±1.3 mmHg) compared to WT+AngII, and was normalized with GR73632 (1.4±0.4 mmHg). LV to tibia ratio (4.3±0.1 vs 3.4±0.1 mg/mm, p<0.0001) and cardiomyocyte cross sectional area (432.5±28 vs 320±25.5 mm 2 , p<0.01) was increased in WT+AngII vs WT+Saline, indicating hypertrophy. These parameters remained increased in Tacr1 -/- +AngII mice (3.7±0.1 mg/mm&428.8±21 mm 2 , p>0.9999 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.
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Schafner et al. (2025) studied Hypertension (n=47). GR73632 (NK1R agonist) vs. Wildtype + Angiotensin II was evaluated on Cardiac fibrosis (%) (p=<0.0001). In a mouse model of hypertension, the NK1R agonist GR73632 normalized cardiac fibrosis (0.3% vs 0.7%, p<0.0001) and diastolic dysfunction compared to untreated hypertensive controls.
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