Aryl Hydrocarbon Receptor is Required for Prevention of Blood Clotting and for the Development of Vasculature and Bone in the Embryos of Medaka Fish, Oryzias latipes

Abstract

The aryl hydrocarbon receptor (AHR) is a member of ligand-activated transcription factors and conserved among vertebrates. To investigate the role of AHR in fish development, medaka embryos were treated with agonist (2,3,7,8-tetrachlorodibenzo-p-dioxin), antagonists (alpha-naphthoflavone and resveratrol), and inhibitor (piperonyl butoxide) of cytochromes (Cyts) P450 encoded by a battery of target genes. These embryos were found to have similar abnormal phenotypes. Among the most consistent phenotypes were blood clotting and malformation of bone that were associated with vascular damages. These results thus indicate that control of AHR is important for proper development of fish embryos. AHR may control levels of Cyts P450 that are responsible for synthesis and metabolism of a toxic compound that caused the abnormal phenotypes. Complementary DNA fragments encoding AHR homologs were cloned from medaka embryos. AHR-specific mRNA was ubiquitously expressed in embryos and adult tissues.

The Role of Aryl Hydrocarbon Receptor in the Pathogenesis of Cardiovascular Diseases

“…Second, the early expression of AhR and ARNT in myocardial chicken embryo suggests that myocardial AhR and ARNT protein expressions may be involved in cardiac signaling during cardiogenesis (Chien et al, 1993;Walker et al, 1997). This was recently supported by several studies that showed that AhR-null mice develop cardiac hypertrophy, ventricular wall thickness, coronary artery hyperplasia, aortic hypertension, elevation of mean arterial pressure, and associated with decreased cardiac output as compared to AhR WT mice (Kawamura and Yamashita, 2002;Lund et al, 2003;Thackaberry et al, 2002;Vasquez et al, 2003).…”

“…Furthermore, studies on medaka fish embryos showed that exposure to TCDD induced vascular damage manifested by vascular hemorrhage and circulation failure. In that study, the TCDD-induced vascular damage was transiently suppressed by treatment with AhR antagonist, aNF, or CYP inhibitor, piperonyl butoxide (PBO), providing convincing evidence of AhR-and CYP-mediated mechanism (Kawamura and Yamashita, 2002) Chronic administration of TCDD or PCB (100 ng/kg/day) for 2 years to SpragueDawley rats was associated with an increased incidence of spontaneous cardiomyopathy (Jokinen et al, 2003). In addition, rats treated acutely with high concentrations of TCDD exhibited cardiac lesions and increased the atrial responsiveness to (-)-isoproterenol, a drug that increases heart rate and heart muscle contractions (Buu-Hoi et al, 1972;Hermansky et al, 1988;Kelling et al, 1987).…”

“…This suggests that the AhR-ARNTmediated signaling pathway plays a vital role in several organ systems. Although the physiological functions of the AhR-ARNT complex in the CVS, in particular, have not been fully investigated, several studies in different animal models have concluded that AhR and ARNT play a functional role in cardiovascular development and homeostasis (Fernandez-Salguero et al, 1997;Kawamura and Yamashita, 2002;Lund et al, 2003;Thackaberry et al, 2002).…”

“…Moreover, a marked increase in the expression of cardiac hypertrophy marker genes, such as b-myosin light chain 2V (bML2V, 50%) and b-myosin heavy chain (bMHC, six fold), but not a-skeletal actin or antinatriuretic peptide (ANP) mRNAs, was associated with these cardiac manifestations (Kanzawa et al, 2004;Kawamura and Yamashita, 2002;Lund et al, 2003;Thackaberry et al, 2002;Thackaberry et al, 2005b;Vasquez et al, 2003). These results strongly suggest that AhR is required for normal cardiovascular homeostasis because the loss of AhR results in cardiac hypertrophy that is probably a result of systemic hypertension.…”

Ginsenoside Rb1 Inhibits Doxorubicin-Triggered H9C2 Cell Apoptosis via Aryl Hydrocarbon Receptor

“…In addition, studies on TCDD exposure to medaka fish embryos showed that TCDD induced vascular hemorrhage and blood clotting. However, the vascular damage could be suppressed by AhR antagonist or CYP inhibitor, further underscoring the role of AhR and CYPs in cardiovascular diseases (Kawamura and Yamashita, 2002). Although there are many studies which have examined the effects of AhR ligands, particularly TCDD, on the cardiovascular system, the mechanisms underlying the cardiotoxic effect of TCDD has not yet been explained definitively.…”