Estrogen Mediated Regulation of miRNA in Cardiac Remodeling

Eastern Kentucky University, Richmond KY

Investigators

Abstract

DESCRIPTION (provided by applicant): This proposal accomplishes the AREA program objectives: 1) supporting meritorious research;2) exposing undergraduates to research;and 3) strengthening the research environment in non-research intensive universities. Approximately 80 million Americans have hypertension. Prolonged hypertension eventually leads to the development of left ventricular hypertrophy (LVH), which is a significant risk factor for cardiovascular death and heart failure (HF). Within the last few years research has shown that microRNAs (miRNAs) are highly regulated during cardiac hypertrophy and are capable of regulating cardiac remodeling. To date no comparison of sex dependent cardiac miRNAs have been described. Sex specific differences in the response of the heart to stressors such as hypertension have been well documented. Estrogen has been shown to play a protective role in this regard in both humans and rodent models. We have demonstrated in a pilot study that selected miRNAs are differentially regulated in male and female mice at baseline and in as a consequence of stimulation of cardiac hypertrophy. An understanding of sex specific regulation of miRNAs in the heart could have a far-reaching impact on the diagnosis and treatment of heart disease. This proposal will test the central hypothesis that male/female differences in susceptibility to adverse cardiac structural remodeling are due to estrogen mediated regulation of miRNAs. The specific aims of this research are 1) to identify miRNAs regulated by estrogen in cardiomyocytes during cardiac remodeling;2) to determine the cell signaling mechanisms through which estrogen regulates miRNAs;and 3) to establish a functional role for miRNAs in estrogen mediated inhibition of cardiomyocyte hypertrophy. Ultimately, the goal of this research is to improve our understanding of the sex specific regulation and downstream targets of miRNAs during cardiomyocyte hypertrophy to improve diagnosis and treatment of LVH. All the experiments outlined in this proposal are designed to engage undergraduates in research. Mentored by the PI, undergraduates will perform experiments, participate in weekly lab meetings, present their research at scientific conferences, and assist in the writing of manuscripts. Our research activities will be visible and shared with our department and university research community through scientific posters on the walls of the science building, the university- wide Undergraduate Showcase, and highlighting research student accomplishments in the EKU Today, a monthly online newsletter. It is intended for this exposure to lead to increased excitement about scientific research and to stimulate EKU undergraduates to participate in research endeavors. PUBLIC HEALTH RELEVANCE: Approximately 80 million Americans have hypertension, which can lead to a thickening of the heart muscle, called left ventricular hypertrophy, and eventually heart failure. The goal of this research is to identify markers (microRNAs) that are specific to males and females during cardiac hypertrophy in rodent models to ultimately aid in the diagnosis and treatment of heart failure. In addition, this research should elucidate the signaling pathways that regulate these miRNAs, as well as pathways that are themselves regulated by these miRNAs.