the aryl hydrocarbon receptor ( ahr ) is a transcription factor that belongs to the basic helix - loop - helix /per - arnt - sim family of dna binding proteins .
there are two major categories of environmental compounds that activate ahr signaling : halogenated aromatic hydrocarbons ( hah ) , such as 2,3,7,8-tetrachlorodibenzo - p - dioxin ( tcdd ) and polycyclic aromatic hydrocarbons ( pah ) , such as benzo(a)pyrene .
unliganded ahr forms a complex including two copies of 90kd a heat shock protein ( hsp90 ) , one x - associated protein ( xap ) , and one p23 molecular chaperone protein in the cytoplasm.[14 ] after being activated by its ligands , cytoplasmic ahr translocates into the nucleus , disassociates from the chaperone complex , dimerizes with the aryl hydrocarbon receptor nuclear translocator ( arnt ) and transactivates target genes through binding to dioxin response elements ( dre ) in promoter regions .
ahr target genes include phase i and phase ii metabolic enzymes , such as cytochrome p450 1a1 ( cyp1a1 ) , cytochrome p450 1b1 ( cyp1b1 ) , nad(p)h : quinone oxidoreductase i ( nqo1 ) and aldehyde dehydrogenase 3 ( alhd3a1 ) [ figure 1 ] .
the induction of xenobiotic metabolizing enzymes following ahr activation is considered , at least in part , an adaptive response of the organism to its environment , which could decrease the potential toxicity of foreign chemicals . on the other hand , activation of ahr
aryl hydrocarbon receptor signaling pathway the ahr molecule varies significantly across species in mediating tcdd toxicity , as well as in molecular weight by almost 30kd , which is primarily due to the different positions of the translational termination codon .
four murine ahr alleles , ahr , ahr , ahr and ahr , have been found and cloned from different inbred and wild mouse strains.[69 ] the ahr receptor has a lower ligand - binding affinity compared to the ahr and ahr alleles .
the ahr allele encodes a protein of 805 amino acids , the ahr and ahr alleles encode proteins of 848 amino acids , and the ahr allele encodes a protein of 883 amino acids .
all proteins of the four alleles contain a basic helix - loop - helix motif ( bhlh ) , per - arnt - sim ( pas ) domain and a transactivation domain ( tad ) , and their varied amino acids exist at the carboxyl end .
human ahr is identical to mouse ahr at n - terminus and has 60% identity with mouse ahr at c - terminus .
an ala375val375 polymorphism is responsible for the reduced ligand - binding affinity of the ahr receptor compared with the ahr receptor in both rodent and human .
aryl hydrocarbon receptor structure through evolution of multicellular organisms , the function of ahr in environmental adaption has also been put to use in important physiological processes .
ahr mrna is expressed in multiple human tissues , with the highest expression in the placenta , relatively high expression in the lung , heart , pancreas and liver , and lowest expression in the kidney , brain and skeletal muscle .
its mrna has also been detected in multiple vascular beds in human , including pulmonary microvasclature , aortic arch and umbilical vein . in the absence of exogenous ligands , the intrinsic activity of ahr
signaling is subject to regulation by either endogenous ligands , including 2-(1h - indole-3-carbonyl)-thiazole- 4-carboxylic acid methyl ester , arachidonic acid metabolites , such as prostaglanding2 and lipoxin4a , and heme metabolites , such as bilirubin ; or nonligand activators , such as shear stress , camp and modified low - density lipoprotein ( ldl).[1422 ] although none of these factors have been proved as high - affinity physiological activators of ahr , the endogenous function of ahr signaling , including heart function , vascular development and blood pressure regulation , has been characterized using ahr gene - deficient mice . due to the nature of ahr , a mediator of xenobiotics and a potential target in genetic modification of cardiovascular function , in this review
, the function of this receptor in the cardiovascular system is summarized and discussed , which may shed light on the development of a new therapeutic methodology in cardiovascular disease prevention and treatment .
in the 1990s , ahr - deficient mice were developed independently in three labs , by either deleting exon 1 or exon 2 of the gene .
all three ahr - null mice had a mixed c57bl/6 129 background and displayed a slower growth rate within the first few weeks after birth , tcdd resistance , failure of xenobiotic cyp1a1 and cyp1a2 induction , maintained but decreased fertility and liver pathology .
ahr - deficient mice develop cardiac hypertrophy and fibrosis in adulthood with a sophisticated mechanism.[2628 ] early characterization of the enlarged heart in ahr - null mice suggested that enhanced vascular endothelial growth factor ( vegf ) expression may contribute to the hypertrophy phenotype . in 2003 , vasquez et al . , reported increased size of cardiomyocytes and an anatomic remodeling without typical features of molecular remodeling , which was not consistent with hypertrophic growth secondary to pressure or volume overload .
this suggested an intrinsic role of ahr in cardiomyocyte size control . in the same year , lund et al .
, indicated that cardiac hypertrophy in ahr - null mice was associated with high systemic arterial blood pressure as well as increased circulating angiotensin ii ( ang ii ) and plasma endothelin-1 ( et-1 ) level .
this cardiac hypertrophic phenotype was primarily mediated by elevated circulating et-1 , thus treatment with bq-123 , an eta receptor antagonist , significantly attenuated the phenotype as well as the mrna expression of cardiac hypertrophy markers , atrial natriuretic factor ( anf ) and -myosin heavy chain ( -mhc ) .
cardiac fibrosis were observed by both groups in ahr - null mice , suggesting a functional remodeling of the heart . a further study on altitude acclimated low blood pressure ahr knockout mice revealed that the hypertrophied heart is more likely a compensatory physiological effect to increase cardiac output in an attempt to increase blood pressure .
this is consistent with the absence of pathological cardiac hypertrophy markers reported by vasquez et al .
a recent study on ahr - null mice also indicated cardiac hypertrophy and fibrosis , which might involve vav3 , an activator of rho / rac gtpases , regulated by ahr .
the authors also demonstrated a thickening of arterial media wall and increased number of vascular smooth muscle cells in arterial walls .
all the research data above , although inconsistently , suggest that local ahr signaling contributes to the development of cardiac hypertrophy and fibrosis that reflects a cardiac functional remodeling .
the role of endogenous ahr in vascular development is also uncovered from the research on ahr knockout mice , which exhibit a spectrum of hepatic defects , including portal fibrosis and a smaller liver .
the mechanism underlying the liver defect seems due to fetal hepatic necrosis caused by compromised perfusion , and partially resulted from a patent ductus venosus in adulthood , which is mediated by loss of ahr in endothelial cells specifically.[3436 ] abnormal vascular structures have also been reported in the liver , kidney and hyaloid of ahr knockout mice .
a further investigation showed that the mice carrying the hypomorphic ahr allele also develop patent ductus venosus , which could be rescued by tcdd treatment .
in addition , nuclear translocation and dna binding abilities of ahr are both required in the closure of ductus venosus , suggesting a transactivation mechanism in this particular endogenous ahr function .
taken together , these two models suggest that the endogenous and exogenous ligand - activated ahr signaling may share the same signal transduction mechanism in mediating vascular development .
the role of the ahr agonist , tcdd , in inducing high blood pressure has been demonstrated in both epidemiology studies and research using mouse models , in which ahr - mediated cytochrome p450 overexpression may be involved.[3943 ] due to the similarity between endogenous and exogenous ahr signaling , it is not surprising that endogenous ahr also contributes to blood pressure regulation in addition to the cardiovascular development mentioned above .
anesthetized ahr - null mice were first found hypotensive in the absence of a heart rate difference at eight months of age . the authors also reported a decreased cardiac output caused by diminished stroke volume in four - month - old ahr knockout mice .
later in the same year , lund et al . , reported high blood pressure in conscious ahr - null mice , associated with elevated circulating ang ii and et-1 levels . in this study ,
angiotensin converting enzyme blockade by captopril attenuated , but did not normalize elevated arterial blood pressure .
subsequently , et-1 was identified as the primary factor causing high arterial blood pressure in those ahr - null mice .
treatment with bq-123 , an eta receptor blocker , dramatically attenuated mean arterial blood pressure as well as plasma ang ii levels in ahr - null mice , suggesting increased ang ii as a secondary effect of et-1 elevation .
another group also reported elevated arterial blood pressure in ahr - null mice , which was normalized by captopril treatment .
their model also suggested an increase of vascular -1d adrenoceptor expression that was involved in the hypertensive phenotype .
interestingly , both groups reported hypertension in ahr - null mice located at mild high altitude ( albuquerque nm , 1620 m ; mexico city , 2240 m ) .
a further investigation of blood pressure in ahr - null mice indicated that loss of endogenous ahr signaling in mice led to hypotension at sea level and hypertension at mild high altitude , which was caused by different atmospheric oxygen levels . a recent study performed by the group in albuquerque comprehensively investigated the role of ahr in blood pressure regulation using ahr heterozygous and null mice .
their up - to - date data indicated a very interesting phenotype of ahr - null mice . after living for a few years at high altitude ,
the ahr null mice have a hypotensive phenotype , which mimics the blood pressure phenotype observed at sea level .
additionally , the former proposed mediators of high blood pressure , including high circulating ang ii and et-1 levels , no longer occur in these animals .
this suggests that the ahr - null mice in albuquerque have physiologically adapted to the altitude and exhibit a blood pressure phenotype consistent with sea level animals .
the hypotensive ahr - null mice exhibit a significantly higher level of endothelial nitric oxide synthase ( enos ) and enhanced vascular nitric oxide ( no ) production compared to both wild - type and ahr heterozygous mice , which both have normal blood pressure .
however , this is not likely the cause of hypotension in ahr - null mice , since n -nitro - l - arginine ( lnna ) , a non - selective nitric oxide synthase ( nos ) blocker , failed to normalize the blood pressure .
moreover , neither prazosin , an alpha1 adrenoceptor antagonist , nor hexamethonium , a ganglionic blocker treatment , causes any differences in the blood pressure change among ahr wild - type , heterozygous and null mice , suggesting an intact sympathetic activity in the blood pressure regulation of ahr - null mice .
however , a research group in spain , salamanca ( 802 m ) compared ahr - null and vav3-null mice , which developed similar cardiovascular remodeling and blood pressure , and suggested that the hypertension of ahr - null mice is mediated by vav3 through a sympathoexcitation mechanism .
although the role of ahr in blood pressure regulation remains to be elucidated , there is no doubt that ahr could serve as a target in the treatment of high blood pressure and other no - dependent vascular diseases .
most cardiovascular diseases are attributed to long term , repeated functional interruption and deposition of harmful factors in the cardiovascular system .
the role of ahr in mediating xenobiotics - induced vascular damage has been well documented .
however , the research results on the role of endogenous ahr in vascular homeostasis and blood pressure regulation still remain contradictory . from all the research on ahr gene - deficient mice
, there is no doubt that ahr is one of the most important factors in maintaining blood pressure stability in those animals .
the mechanism of more than 90% of the cases of human hypertension is unknown and ahr gene polymorphism has been detected in humans .
therefore epidemiology research to correlate ahr gene polymorphism , altitude of residence and blood pressure phenotype will provide valuable insight into the role of ahr in human blood pressure control . on the other hand ,
further understanding of the role of ahr in no generation in vasculature endothelium and vascular remodeling will also contribute to the prevention of vascular diseases , such as atherosclerosis .
the nature of cardiovascular diseases suggests a multifactorial etiology and a long - lasting disease development process .
the endogenous ahr signaling represents a very promising target for cardiovascular disease prevention and treatment due to its role in heart and vascular physiology , blood pressure regulation and vascular no generation .
thus , the ahr function in the cardiovascular system requires careful and comprehensive investigation with employment of true littermate animals with a pure genetic background and well - controlled animal husbandry environment .
 the aryl hydrocarbon receptor ( ahr ) is an orphan nuclear receptor with a primary function of mediating xenobiotic metabolism through transcriptional activation of phase i and phase ii drug - metabolizing enzymes . 
 although no high - affinity physiological activators of ahr have been discovered , the endogenous signaling of the ahr pathway is believed to play an important role in the development and function of the cardiovascular system , based on the observations on ahr gene - deficient mice . 
 the ahr knockout mice develop cardiac hypertrophy , abnormal vascular structure in multiple organs and altered blood pressure depending on their host environment . in this review , the endogenous role of ahr in cardiovascular physiology , including heart function , 
 vascular development and blood pressure regulation has been summarized and discussed . 
INTRODUCTION
ARYL HYDROCARBON RECEPTOR IN HEART FUNCTION
ARYL HYDROCARBON RECEPTOR IN VASCULAR DEVELOPMENT
ARYL HYDROCARBON RECEPTOR IN BLOOD PRESSURE REGULATION
CONCLUSIONS