Grantee Research Project Results
Final Report: The Role of Endothelin-1 Regulation and Expression in Cardiac Hypertrophy Observed in Aryl Hydrocarbon (AhR) Null Mice
EPA Grant Number: U916215Title: The Role of Endothelin-1 Regulation and Expression in Cardiac Hypertrophy Observed in Aryl Hydrocarbon (AhR) Null Mice
Investigators: Lund, Amie K.
Institution: University of New Mexico
EPA Project Officer: Hahn, Intaek
Project Period: January 1, 2003 through January 1, 2006
Project Amount: $115,244
RFA: Minority Academic Institutions (MAI) Fellowships for Graduate Environmental Study (2003) RFA Text | Recipients Lists
Research Category: Academic Fellowships , Fellowship - Natural and Life Sciences , Biology/Life Sciences
Summary/Accomplishments (Outputs/Outcomes):
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 endothelin-1 (ET-1) and angiotensin II (Ang II), and reactive oxygen species (ROS). 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; expression of cardiac hypertrophy marker genes ( atrial natriuretic factor, β-myosin heavy chain, β-myosin light chain 2V); echocardiographical measurements; as well as by presence of cardiac fibrosis. 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.
Experimental data revealed that cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice is associated with elevated ET-1, Ang II, MAP and reactive oxygen species (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, ET A receptor antagonism resulted in attenuation of MAP, ET-1, Ang II and normalization of cardiac parameters in AhR null mice. Additionally, ET A 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 and blood pressure, 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-ET A receptor activation. Given that human exposure to AhR agonists (i.e. environmental pollutant TCDD) have been correlated to an increased risk of cardiovascular events; and that recent studies have identified endogenous ligands of the AhR, future studies which further elucidate the role of AhR in cardiovascular physiology may provide signaling pathways which serve as mediators of the induction or progression of cardiac hypertrophy. Such research will likely lead to potential targets for drug therapies to prevent the progression of disease states associated with exposure to certain environmental pollutants.
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.