What is the clinical evidence from this study?

Study design: Other. Population: Cardiac remodeling and fibrosis (n=20). Intervention: SP1-9 (MRGPRB2 agonist) vs. Saline. Primary outcome: Left ventricular end diastolic pressure (p=0.0025).

What does this research mean for the field?

Activation of the MRGPRX2/B2 receptor with SP1-9 increases left ventricular end-diastolic pressure and decreases cardiac output, leading to cardiac dysfunction and a pro-inflammatory mast cell phenotype. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The central aim was to determine if MRGPRX2 activation on mast cells leads to a proinflammatory phenotype.

May 14, 2026

MRGPRX2 Activation Worsens Adverse Cardiac Remodeling and Causes Mast Cell Degranulation

Key Result

Activation of MRGPRX2/B2 with SP1-9 in mice increased left ventricular end diastolic pressure (3.1 vs 1.2, p=0.0025) and decreased cardiac output, leading to cardiac dysfunction.

Key Points

The central aim was to determine if MRGPRX2 activation on mast cells leads to a proinflammatory phenotype.
Used a mouse model and a mast cell cell culture model with 8-week-old male mice.
Injected mice with either saline or MRGPRB2 agonist SP1-9 for 14 days; assessed left ventricular function using pressure volume analysis.
Treated LAD2 human mast cells with various substance P metabolites to evaluate histamine and TNF release.
SP1-9 significantly increased left ventricular end diastolic pressure (3.1±1.9 vs 1.2±0.4, p=0.0025) and stiffness constant Tau (6.8±0.9 vs 4.6±0.9, p<0.0001).
Chronic treatment with SP and SP1-9 increased TNF release (SP: 0.0 vs 58.4 pg/mL, p<0.0001; SP1-9: 0.0 vs 58.4 pg/mL, p=0.0009) and CCL2 levels (both SP and SP1-9 had p<0.0001).

Structured PICO

Population

8-week-old male wildtype (WT) mice (n=20) and Laboratory of Allergenic Disease 2 (LAD2) human mast cells (n=8/group)

Intervention

MRGPRB2 agonist SP1-9 (600mg/kg/day) subcutaneous injection daily for 14 days (in vivo); SP and SP metabolites (SP6-11, SP1-9, 10uM) for 30 min or 4 hr (in vitro)

Comparator

Subcutaneous injection of saline (in vivo); control (in vitro)

Outcome

Left ventricular (LV) function (LVEDP, Tau, cardiac output) and mast cell degranulation/proinflammatory cytokine release (histamine, TNF, CCL2)surrogate

Activation of the MRGPRX2/B2 receptor by substance P metabolite SP1-9 induces a proinflammatory mast cell phenotype and cardiac dysfunction, identifying it as a potential profibrotic target.

Main Result

Absolute Event Rate: 3.1% vs 1.2%

p-value: p=0.0025

Abstract

The neuropeptide substance P (SP) induces pro- and anti-fibrotic responses in the heart. SP activates the neurokinin 1 receptor (NK1R) and a novel SP receptor, the Mas-related G protein coupled receptor X2 (MRGPRX2). In the diabetic heart, SP is antifibrotic and treatment with the NK1R agonist, GR73632, prevents cardiac fibrosis and cardiac dysfunction. In the hypertensive heart, SP is profibrotic, but NK1R activation prevents cardiac fibrosis and cardiac dysfunction. Therefore, another receptor must be responsible for SPs pro-fibrotic effects. We hypothesize that MRGPRX2, mouse ortholog MRGPRB2, is the profibrotic SP receptor because it is exclusively found on mast cells (MCs) and MCs are profibrotic. The objective of this study was to determine if MRGPRX2 activation on MCs leads to a proinflammatory MC phenotype. To begin investigating if MRGPRX2 (MRGPRB2 in mice) is the profibrotic SP receptor, a mouse model and a MC cell culture model was used. 8-week-old male wildtype (WT) mice received subcutaneous injection of saline (n=10) or a MRGPRB2 agonist, SP1-9 (600mg/kg/day, n=10) daily for 14 days. Left ventricular (LV) function was determined by pressure volume analysis. Laboratory of Allergenic Disease 2 (LAD2) human MCs were treated with SP and SP metabolites (SP6-11, SP1-9, 10uM, n=8/group) for 30 min (rapid degranulation) or 4 hr (de novo synthesis). SP activates the NK1R and MRGPRX2 while SP6-11 only activates the NK1R, and SP1-9 only MRGPRX2. At 30 min, SP, SP6-11, and SP1-9 all induced histamine release from LAD2 cells. At 4 hr, SP (0.0±0.0 vs 37.64±7.4 pg/mL, p< 0.0001 vs control) and SP1-9 increased TNF release (0.0±0.0 vs 58.4±11.9 pg/mL, p< 0.0001 vs control). SP6-11 did not alter TNF release. SP1-9 elicited a greater TNF response than SP (p=0.0009). Also at 4 hours, SP (282.5±113.3 vs 1723.0±176.9 pg/mL, p< 0.0001) and SP1-9 (282.5±113.3 vs 1678.0±628.1 pg/mL, p< 0.0001) increased CCL2 release. SP6-11 had no effect. We then tested the effect of SP1-9 in vivo. LV end diastolic pressure was increased in SP1-9 mice vs Saline (3.1±1.9 vs 1.2±0.4, p=0.0025). The stiffness constant Tau was also increased in SP1-9 mice vs Saline (6.8±0.9 vs 4.6±0.9, p< 0.0001). Cardiac output was decreased in SP1-9 mice vs Saline (5895±902 vs 8419±1310, p=0.0005). Overall, chronic treatment of LAD2 MCs with SP and SP1-9 led to a proinflammatory MC phenotype as indicated by increased of both TNF and CCL2. This did not occur in response to SP6-11, which is a ligand for the antifibrotic NK1R, and further indicates that the NK1R is antifibrotic in the heart. Activating MRGPRX/B2 in mice with SP1-9 led to cardiac dysfunction. While further studies are required, these initial findings indicate that MRGPRX2 may be the profibrotic SP receptor. Funding for this project is supported by the NIH (DK142329). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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