Grantee Research Project Results

The Role of Endothelin-1 Regulation and Expression in Cardiac Hypertrophy Observed in Aryl Hydrocarbon (AhR) Null Mice

EPA Grant Number: U916215
Title: 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: Biology/Life Sciences , Fellowship - Natural and Life Sciences , Academic Fellowships

Objective:

The objective of this research project is to determine the role of the Aryl hydrocarbon receptor (AhR) in cardiovascular physiology and homeostasis. The AhR is a ligand-activated transcription factor, which is known to mediate the toxicity of several environmental pollutants. Additionally, pathological studies of AhR null mice suggest a role for AhR in normal development and homeostasis of the heart. Specifically, these experiments will attempt to elucidate the etiology of cardiac hypertrophy observed in AhR null mice. We have previously shown that AhR null mice exhibit elevated plasma levels of the vasoactive peptides endothelin-1 (ET-1) and angiotensin II (Ang II), in association with elevated mitogen-activated protein (MAP). The hypothesis that will be investigated is that a genetic deletion of the AhR induces ET-1, resulting in hypertension and cardiac hypertrophy. Furthermore, we will elucidate whether reactive oxygen species (ROS) are associated with the cardiac hypertrophy observed in AhR null mice.

Approach:

To fully understand the role of ET-1 and MAP in the progression of cardiac hypertrophy seen in AhR null mice, we must first elucidate the primary source of ET-1 as well as determine whether loss of the AhR deregulates the expression of ET-1 in a tissue-specific manner. To complete this, we will first establish whether induction of ET-1 results in elevation in MAP and cardiac hypertrophy, utilizing an AhR null mouse model. Briefly, mice will be treated with an ETA-receptor antagonist, and resulting MAP measurements will be taken. Cardiac and renal tissue samples from the animals in this research project also will be used to assess expression of hypertrophy markers (cardiac) and fibrosis (cardiac and renal). This research project will elucidate whether the loss of AhR results in the deregulation of ET-1 expression in a tissue-specific manner. This will involve both immunohistochemical and mRNA expression analysis of the heart, kidney, and lung tissue. Additionally, we also will investigate whether the loss of AhR deregulates ET-1 transcriptional expression in endothelial cells, utilizing primary endothelial cell cultures. We will focus on measuring ROS levels in the hearts of AhR null mice, as well as those that have been treated with an ETA-receptor antagonist. This will determine if ROS are correlated to the observed cardiac hypertrophy and whether the induction of ROS is associated with ET-1 expression.

We expect that by blocking the effects of ET-1 on the cardiovascular system, we can effectively reduce the elevated MAP, ROS, and cardiac hypertrophy in AhR null mice. Additionally, we expect to gain further insight into the endogenous functions of the AhR through these experiments. It is valuable to utilize methods involving the knockout of the AhR gene to gain a more thorough understanding of the normal physiological roles of the AhR in cardiovascular homeostasis.

Supplemental Keywords:

fellowship, Aryl hydrocarbon receptor, AhR, endothelin-1, ET-1, cardiac hypertrophy, reactive oxygen species, ROS, mitogen-activated protein, MAP.

Progress and Final Reports:

2003

2004

Final Report