ABSTRACT
OBJECTIVES: Recent evidence indicates that suppressing inflammation by specific drug target and treatment measures contributes to attenuate ischaemic injury and the related heart diseases. This study aimed to investigate the potential effect of baicalin on myocardial ischaemic injury through inhibition of inflammation by inactivating the aryl hydrocarbon receptor (AhR). METHODS: The mouse model with myocardial ischaemic injury was prepared by the left anterior descending coronary artery-amputation and then treated using baicalin. After observing the expression of AhR by immunohistochemical staining, the AhR and inflammatory mediators in circulation and myocardial tissues, including high-sensitive C-reactive protein (hsCRP), interleukin (IL)-1ß and IL-6, were detected based on enzyme-linked immunosorbent assay, real-time polymerase chain reaction and Western blot methods. KEY FINDINGS: The results showed that (1) substantial expression of AhR was observed in myocardial tissues; (2) ischaemic injury caused myocardial necrosis and remodelling, and stimulated hsCRP, IL-1ß and IL-6 by activation of AhR; and (3) baicalin alleviated the myocardial injury and inflammatory response by inhibiting the expression of AhR. CONCLUSION: Our findings extend the list of AhR ligands beyond exogenous toxins and endogenous molecules to cardiac immunological factors, and moreover it could be considered potential drug targets due to its pathological modulatory properties, while baicalin demonstrated promise as a novel vehicle for ischaemic heart disease.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Flavonoids/pharmacology , Myocardial Ischemia/prevention & control , Myocarditis/prevention & control , Myocytes, Cardiac/drug effects , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , C-Reactive Protein/metabolism , Disease Models, Animal , Inflammation Mediators/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Male , Mice , Myocardial Ischemia/genetics , Myocardial Ischemia/metabolism , Myocardial Ischemia/pathology , Myocarditis/metabolism , Myocarditis/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Necrosis , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction/drug effects , Ventricular Remodeling/drug effectsABSTRACT
The aryl hydrocarbon receptor (AhR) mediates the control of environmental toxicity, and modulates the development and pathogenesis of the cardiovascular system. However, little is known about the role of AhR in coronary arterial disease (CAD) susceptibility. We therefore conducted a case-control study in a Chinese population, and assessed the potential association between AhR variants and CAD susceptibility. Compared with the controls, circulating AhR expression was found to be significantly increased in patients with CAD and its subtypes including ST-segment and non-ST-segment elevation myocardial infarction, and stable and unstable angina pectoris. Receiver operating characteristic (ROC) analysis to evaluate the effect of AhR on CAD progression showed it to be a potent biomarker for CAD. Genotype frequencies of AhR rs2066853 differed significantly between CAD and control subjects, while smoking and hyperlipidemia markedly promoted CAD risk relative to the AhR polymorphism. Moreover, a significant difference in AhR variant distribution was observed between the four CAD subtypes with different severities. The expression level and functional polymorphisms of circulating AhR may affect the susceptibility and progression of CAD in Chinese populations. This provides a novel view of the etiology and epidemiology of CAD, and will contribute to the diagnosis and therapy of this severe disease.
Subject(s)
Coronary Artery Disease/genetics , Genetic Association Studies , Receptors, Aryl Hydrocarbon/genetics , Aged , Coronary Artery Disease/blood , Coronary Artery Disease/pathology , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Receptors, Aryl Hydrocarbon/blood , Risk FactorsABSTRACT
OBJECTIVES: Baicalin, a natural flavone, has antithrombotic, antihyperlipidemic and antiinflammortory activity. It can also inhibit cancer cell proliferation and reduce brain cell apoptosis. This study aimed to elucidate the effect of baicalin on the excessive proliferation of human pulmonary arterial smooth muscle cells (HPASMCs) induced by transforming growth factor-ß1 (TGF-ß1) and to investigate the roles of hypoxia inducible factor-1α (HIF-1α) and aryl hydrocarbon receptor (AhR) in mediating this TGF-ß1-induced excessive proliferation of HPASMCs. METHODS: TGF-ß1-induced proliferation of HPASMCs was assayed using the CCK8 method. The cellular phenotype was identified by immunocytochemical staining. Expression of HIF-1α and AhR mRNA was determined by real-time quantitative PCR. KEY FINDINGS: TGF-ß1 promoted significantly HPASMC proliferation (P < 0.05) and induced a phenotypic switch from the contractile to synthetic type. Baicalin inhibited this TGF-ß1-induced phenotypic switch and consequently the excessive growth of HPASMCs in a time-dependent and dose-dependent manner (P < 0.05). Furthermore, baicalin attenuated the abnormal proliferation of HPASMCs through suppression of the HIF-1α and AhR pathways. CONCLUSIONS: Our study shows that baicalin has the potential to be used as a novel drug in the treatment of pulmonary arterial hypertension pathology by antagonizing HIF-1α and AhR expression and subsequently decreasing HPASMC proliferation and the phenotypic switch.
