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

Abstract

Numerous experimental and epidemiological studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs), which are major constituents of cigarette tobacco tar, are strongly involved in the pathogenesis of the cardiovascular diseases (CVDs). Knowing that PAH-induced toxicities are mediated by the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR), which regulates the expression of a group of xenobiotic metabolizing enzymes (XMEs) such as CYP1A1, CYP1A2, CYP1B1, NQO1, and GSTA1, suggests a direct link between AhR-regulated XMEs and CVDs. Therefore, identifying the localization and expression of the AhR and its regulated XMEs in the cardiovascular system (CVS) is of major importance in understanding their physiological and pathological roles. Generally, it was believed that the levels of AhR-regulated XMEs are lower in the CVS than in the liver; however, it has been shown that similar or even higher levels of expression are demonstrated in the CVS in a tissue- and species-specific manner. Moreover, most, if not all, AhR-regulated XMEs are differentially expressed in most of the CVS, particularly in the endothelium cells, aorta, coronary arteries, and ventricles. Although the exact mechanisms of PAH-mediated cardiotoxicity are not fully understood, several mechanisms are proposed. Generally, induction of CYP1A1, CYP1A2, and CYP1B1 is considered cardiotoxic through generating reactive oxygen species (ROS), DNA adducts, and endogenous arachidonic acid metabolites. However the cardioprotective properties of NQO1 and GSTA1 are mainly attributed to the antioxidant effect by decreasing ROS and increasing the levels of endogenous antioxidants. This review provides a clear understanding of the role of AhR and its regulated XMEs in the pathogenesis of CVDs, in which imbalance in the expression of cardioprotective and cardiotoxic XMEs is the main determinant of PAH-mediated cardiotoxicity.

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…CYP1B1 is expressed in nonhepatic tissues, including cardiovascular tissues and blood cells. 41,42 We observed that circulating monocytes (CD11b þ ) and T cells (CD3 þ ) from Ang IIeinfused Apoe À/À Cyp1b1 þ/þ mice had enhanced expression of CCR2 (CD192 þ ), which was diminished in mice treated with TMS or in Apoe À/À /Cyp1b1 À/À mice. CCR2 expression is associated with recruitment of monocytes and T cells to the site of inflammation.…”

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

“…12,14 We report that IAA increases ROS production, which was moderately decreased by the AhR inhibitor, suggesting the involvement of other pathways. In addition to CYP1, several sources of ROS exist, notably the mitochondrial electron transport chain, nicotinamide adenine dinucleotide phosphate-oxidase, and cyclooxygenases.…”

“…11 AhR activation by exogenous ligands promotes vascular inflammation, oxidative stress, 5,12 and atherosclerosis 13 and plays a role in cardiovascular diseases. 14 However, the vascular toxicity of IAA has not been thoroughly studied. We recently reported that IAA induces endothelial tissue factor expression, leading to a procoagulant effect, 9 and increases the mRNA expression of the enzyme cyclooxygenase-2 (COX-2), which is primarily responsible for the synthesis of inflammatory prostanoids.…”

Differential Proteomics Analysis Reveals a Role for E2F2 in the Regulation of the Ahr Pathway in T Lymphocytes

“…Ahr/Arnt (41,42) and are used as reporters of Ahr function. Expression levels of these two proteins were analyzed by Western blots to search for differences between WT and E2F2-deficient T lymphocytes.…”