Rutaecarpine mediates phenotypic transition of vascular smooth muscle cells via ADAM17-TNF-NLRP3 signaling pathway

Q: What are the key findings of this study?

Rutaecarpine (10 μmol/L) significantly inhibited Angiotensin II-induced vascular smooth muscle cell phenotypic transition and inflammation via the ADAM17-TNF-NLRP3 pathway in vitro (p<0.01).

Q: What is the clinical evidence from this study?

Population: Hypertension / Vascular smooth muscle cell phenotypic transition. Intervention: Rutaecarpine vs. Angiotensin II stimulation without rutaecarpine. Primary outcome: Angiotensin II-induced VSMC phenotypic transition (cell viability and expression of contractile markers ACTA2 and MYH11) (p=<0.01).

Q: What does this research mean for the field?

Rutaecarpine prevents Angiotensin II-induced vascular smooth muscle cell phenotypic transition and inflammation by inhibiting the ADAM17-TNF-NLRP3 signaling pathway. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To investigate the inhibitory effect and molecular mechanisms of rutaecarpine on angiotensin II-induced vascular smooth muscle cell phenotypic transition.

Hai-Hong Tian; Ying Liu; Pei-Qi Shi; Yan Yang; Yanfang Chen; Chun Zhou; Siyu Zeng

doi:10.21203/rs.3.rs-11041215/v1

October 20, 2026Open Access

Rutaecarpine mediates phenotypic transition of vascular smooth muscle cells via ADAM17-TNF-NLRP3 signaling pathway

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Key result

Rutaecarpine inhibits Ang II-induced VSMC phenotypic switching and inflammation via the ADAM17-TNF-NLRP3 pathway.

P<0.01

Why the study?

Although rutaecarpine inhibits pressure overload-induced vascular remodeling, its role and underlying mechanisms in preventing angiotensin II-induced vascular smooth muscle cell phenotypic transition required further elucidation.

Does rutaecarpine inhibit angiotensin II-induced phenotypic transition in cultured rat vascular smooth muscle cells via the ADAM17-TNF-NLRP3 signaling pathway?

Key Points

To investigate the inhibitory effect and molecular mechanisms of rutaecarpine on angiotensin II-induced vascular smooth muscle cell phenotypic transition.
Evaluated cultured vascular smooth muscle cells stimulated with angiotensin II in vitro.
Applied interventions including 30-minute pretreatment with 10 μmol/L rutaecarpine, ADAM17 siRNA transfection, the TNF inhibitor etanercept, and the NLRP3 inhibitor MCC950.
Assessed cell viability using the Cell Counting Kit-8, contractile markers (ACTA2 and MYH11), and inflammatory cytokine expression (TNF-α, IL-1β, and IL-6).
Pretreatment with 10 μmol/L rutaecarpine for 30 minutes inhibited angiotensin II-induced phenotypic transition, decreasing cell viability and contractile markers ACTA2 and MYH11.
ADAM17 deletion via siRNA or TNF inhibition via etanercept prevented angiotensin II-induced cell proliferation, increased ACTA2 and MYH11 levels, and suppressed NLRP3, IL-1β, and IL-6 levels.
Rutaecarpine treatment suppressed angiotensin II-induced ADAM17 protein levels, TNF-α mRNA levels, NLRP3 protein levels, and mRNA levels of IL-1β and IL-6.

Structured PICO

Does rutaecarpine inhibit angiotensin II-induced phenotypic transition in cultured rat vascular smooth muscle cells via the ADAM17-TNF-NLRP3 signaling pathway?

P

Population

In vitro rat vascular smooth muscle cells (A7R5 cell line, n = 4 independent experiments per assay) stimulated with 100 nmol/L Angiotensin II for 24 hours.

I

Intervention

Pretreatment with 10 μmol/L rutaecarpine for 30 minutes prior to Ang II stimulation; mechanistic arms also included transfection with 100 nmol/L rat ADAM17 siRNA, treatment with TNF inhibitor etanercept, or treatment with NLRP3 inflammasome inhibitor MCC950.

C

Comparator

Untreated control cells, Ang II-stimulated VSMCs without rutaecarpine, and scrambled siRNA negative control.

O

Outcome

Inhibition of Ang II-induced VSMC phenotypic transition, assessed via cell viability (Cell Counting Kit-8 assay) and protein expression levels of contractile markers ACTA2 and MYH11 (Western blot).surrogate

Main Result

p-value: p=<0.01

This preclinical study demonstrates that rutaecarpine prevents angiotensin II-induced vascular smooth muscle cell phenotypic transition in vitro by inhibiting the ADAM17-TNF-NLRP3 inflammatory signaling axis, elucidating a potential cellular mechanism for preventing hypertensive vascular remodeling.

Limitations

In vitro cell culture study only; did not examine whether rutaecarpine prevents the ADAM17-TNF positive feedback loop and NLRP3 inflammasome-induced inflammation in the arteries of in vivo hypertensive animal models.
Did not assess downstream markers of inflammasome activation such as caspase-1 cleavage.
Additional studies are needed to confirm whether the positive feedback loop between ADAM17 and TNF directly underlies the beneficial effect of rutaecarpine on VSMC phenotypic transition.
Did not assess downstream markers of inflammasome activation (e.g., caspase-1 cleavage).
In vitro study only; did not examine whether rutaecarpine treatment prevents the ADAM17-TNF positive feedback loop and subsequent NLRP3 inflammasome-induced inflammation in the arteries of in vivo hypertensive animal models.
Additional studies are needed to further confirm whether the positive feedback loop directly underlies the beneficial effect of rutaecarpine on VSMC phenotypic transition.

Implication

Rutaecarpine effects remain limited to cell culture; leaves open translation of ADAM17-TNF-NLRP3 inhibition to in vivo or clinical vascular disease.

Abstract

The Chinese herbal monomer rutaecarpine is extracted from Evodia rutaecarpa, which has been widely used for hundreds of years to treat hypertension. Rutaecarpine can inhibit pressure overload-induced vascular remodeling and oxidized low-density lipoprotein-induced phenotype transition in vascular smooth muscle cells (VSMCs). However, further studies are needed to elucidate the role of rutaecarpine in preventing VSMC phenotypic transition and its underlying mechanisms. This study aimed to explore the inhibitory effect of rutaecarpine on angiotensin (Ang) II-induced VSMC phenotypic transition and its mechanisms. In vitro experiments revealed that rutaecarpine inhibited Ang II- induced VSMC phenotypic transition. Further studies revealed that a disintegrin and metalloproteinase 17 (ADAM17) mediated Ang II- induced VSMC phenotypic transition through tumor necrosis factor (TNF)-NLRP3 signaling pathway. Moreover, treatment with rutaecarpine could inhibit the ADAM17 -TNF-NLRP3 signaling pathway in VSMCs stimulated with Ang II. In conclusion, rutaecarpine prevents Ang II- induced VSMC phenotypic transition via the ADAM17- TNF-NLRP3 signaling pathway.

Discussion

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Cite This Study

Tian et al. (2026) studied Hypertension / Vascular smooth muscle cell phenotypic transition. Rutaecarpine vs. Angiotensin II stimulation without rutaecarpine was evaluated on Angiotensin II-induced VSMC phenotypic transition (cell viability and expression of contractile markers ACTA2 and MYH11) (p=<0.01). Rutaecarpine (10 μmol/L) significantly inhibited Angiotensin II-induced vascular smooth muscle cell phenotypic transition and inflammation via the ADAM17-TNF-NLRP3 pathway in vitro (p<0.01).

synapsesocial.com/papers/6ae28f3dcbadf70daf6c4446 https://doi.org/10.21203/rs.3.rs-11041215/v1

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Rutaecarpine mediates phenotypic transition of vascular smooth muscle cells via ADAM17-TNF-NLRP3 signaling pathway

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Rutaecarpine mediates phenotypic transition of vascular smooth muscle cells via ADAM17-TNF-NLRP3 signaling pathway

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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