Related Experiment Video

Updated: Sep 10, 2025

Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion

Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion

Published on: May 16, 2025

Genistein ameliorates thoracic aortic dissection by inhibiting CB1 receptor hyperactivation and modulating

Yanbang Chi¹, Tao Huang², Jikai Zhao²

¹Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, 21 Shenyang, 110016, PR China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology

|August 22, 2025

Abstract

Background:

Thoracic aortic dissection (TAD) is a fatal cardiovascular disease characterized by vascular smooth muscle cell (VSMC) phenotypic remodeling and inflammation. Cannabinoid 1 (CB1/Cnr1) receptor has been implicated in cardiovascular diseases, but its role in TAD and its downstream signaling remains unclear. Genistein (Gen), an isoflavone abundant in legumes, has demonstrated promising therapeutic potential in cardiovascular diseases such as vascular calcification, hypertension, and atherosclerosis due to its anti-inflammatory, antioxidant, and metabolic regulatory properties. However, the role of Gen in the progression of TAD remains poorly understood.

Purpose:

The present study was designed to investigate the potential of Gen in alleviating medial degeneration and delaying TAD progression by inhibiting the CB1 receptor and modulating its associated cAMP-PKA signaling.

Methods:

In vitro and in vivo experiments evaluated the effects of AM251, a selective CB1 receptor antagonist, and genistein (Gen), a natural CB1 receptor inhibitor, on VSMC remodeling, NLRP3-mediated pyroptosis, and TAD progression. The involvement of cAMP-PKA signaling was validated using the PKA inhibitor H-89.

Results:

CB1 receptor was highly expressed in VSMCs and significantly upregulated in TAD group, while cAMP-PKA signaling was suppressed. Elevated CB1 receptor expression correlated with increased NLRP3-mediated pyroptosis and enhanced VSMC phenotypic modulation. AM251 and Gen treatment restored cAMP-PKA signaling, reduced pyroptosis, and preserved the contractile phenotype of VSMCs, thereby delaying TAD progression. However, overexpression of CB1 receptor diminished the beneficial effects of Gen treatment in VSMCs. Single-cell RNA sequencing further confirmed that Gen reversed the CB1 receptor -induced suppression of cAMP-PKA signaling and mitigated VSMC remodeling. Notably, the protective effects of Gen were abrogated upon PKA inhibition by H-89, highlighting the essential role of cAMP-PKA activation. In vivo, Gen administration significantly reduced TAD incidence, improved aortic wall integrity, and decreased inflammatory cell infiltration.

Conclusion:

CB1 receptor overexpression contributes to TAD development by suppressing cAMP-PKA signaling, promoting pyroptosis, and inducing VSMC remodeling. Genistein exerts protective effects via CB1 receptor inhibition and cAMP-PKA upregulation, suggesting CB1 receptor as a promising therapeutic target for TAD.

Keywords:

CB1 Genistein PKA Thoracic aortic dissection Vascular smooth muscle cell

More Related Videos

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

Published on: September 28, 2015

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

Related Concept Videos

GPCRs Regulate Adenylyl Cylase Activity

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...

Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists

Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists

Endothelins (ETs) are potent vasoactive peptides critical in the human body's various physiological and pathological processes. One of the most promising therapeutic strategies for treating pulmonary arterial hypertension (PAH) involves counteracting the effects of these endothelins using a class of drugs known as endothelin receptor antagonists.
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...

Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists

Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists

Prostacyclin receptor agonists are a class of therapeutic agents integral to managing pulmonary arterial hypertension (PAH). These drugs operate by mimicking the action of prostaglandin I2, or PGI2, a naturally occurring compound in the body.
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...

GPCR Desensitization

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...

Transducer Mechanism: Enzyme-Linked Receptors

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:

Articles linked to this work by shared authors, journal, and citation graph.

Ultrathin carbon nanomesh enriched with highly exposed para-position ZnN2 moiety for effective oxygen electroreduction.

Journal of colloid and interface science·2026

[Exploration of clinical diagnosis and treatment thinking of acupuncture-moxibustion based on the "meridian and zang-fu correlation" theory].

Zhongguo zhen jiu = Chinese acupuncture & moxibustion·2026

Constitutive Modeling of the Nonlinear Tensile Response of High-Strength Nanofiber Yarns Under Monotonic Loading.

Polymers·2026

Entanglement Transition in Unitary System-Bath Dynamics.

Physical review letters·2026

Constructing Fe3N/MnO heterojunction via heteroatom doping for degrading dye wastewater by heterogeneous electro-fenton system.

Journal of environmental sciences (China)·2026

Activation of peroxymonosulfate by distillers' grains biochar for the degradation of ciprofloxacin: critical roles of singlet oxygen and electron transfer.

RSC advances·2026

See all related articles