| The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to mediate the toxicity of environmental pollutants such as 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). The role of the AhR in physiological homeostasis is still uncertain, however functional inactivation of the AhR (as seen in AhR null mice) results in profound effects on the cardiovascular system, characterized by progressive cardiac hypertrophy.; In an effort to elucidate the factors which mediate cardiac hypertrophy in AhR null mice we investigated the potential roles of mean arterial blood pressure (MAP), vasoactive peptides endothelia-1 (ET-1) and angiotensin II (Ang II), and reactive oxygen species (R.US). Indwelling catheters were utilized to assess conscious MAP, while radio immunoassays and real time RT-PCR were used to assess plasma and tissue Ang II and ET-1, respectively. Cardiac hypertrophy was characterized by cardiac weight (normalized to body weight); expression of cardiac hypertrophy marker genes (atrial natriuretic factor, beta-myosin heavy chain, beta-myosin light chain 2V); echocardiographical measurements; as well as by presence of cardiac fibrosis (histochemical analysis and expression of cardiac fibrosis marker genes---osteopontin and collagen I). To differentiate the individual contribution of Ang II and ET-1 in the progression of cardiac hypertrophy in AhR null mice, we utilized in vivo models of chronic pharmacological therapies (ACE inhibitor, captopril; ET receptor antagonist, BQ-123) to attenuate the effects of each of these peptides on the heart.; The data reported, herein, reveal that cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice is associated with elevated ET-1, Ang II, MAP and ROS. While chronic treatment of AhR null mice with an ACE-inhibitor reduced cardiac parameters, it did not normalize MAP, ET-1, or cardiac measurements. Conversely, ETA receptor antagonism resulted in attenuation of MAP, ET-1, Ang II and normalization of cardiac parameters in AhR null mice. Additionally, ETA receptor blockade also markedly reduced ROS levels and NAD(P)H oxidase activation in the myocardium of AhR null mice.; Taken together, these results suggest that cardiac hypertrophy in AhR null mice is primarily mediated through ET-1-mediated signaling pathways, which involve upregulation of Ang II and ROS. Furthermore, these signaling pathways appear to be mediated through ET-1-ETA receptor activation. |
