Pathological hypertrophy is a common but not universal predecessor to heart failure (HF). The heart also grows in response to exercise but this growth, termed physiological hypertrophy, does not generally lead to adverse consequences and can even protect the heart against pathological stress. Moreover, recent work from our group demonstrates that exercise substantially enhances endogenous cardiomyogenesis in the adult heart. There is a fundamental gap in our understanding of how exercise mediates its benefits, including a proliferative and potentially regenerative response in cardiomyocytes, and why cardiac hypertrophy can have such different outcomes. Our over-arching hypothesis is that there are distinct forms of hypertrophy, which appear superficially similar but employ fundamentally different mechanisms and thus have dramatically different outcomes. Our long-term goal is to understand the pathways responsible for these differences and learn whether they can be exploited therapeutically. The objective of the current application is to understand the role of long noncoding RNAs (lncRNAs) in exercise-associated cardiac phenotypes. In preliminary studies, we identified 25 cardiac lncRNAs dynamically regulated by exercise, which we term long noncoding Exercise Associated Transcripts or lncExACTs. Consistent with our over-arching hypothesis, of the 25 lncExACTs identified, none change concordantly in exercise and pathological hypertrophy or HF. Five lncExACTs are also altered in the disease models ? but in opposite directions compared to exercise. One of these, lncExACT1, is particularly intriguing because it decreases in exercised hearts and increases both in animal HF models and human HF. Our preliminary data with lncExACT1 gain- and loss-of-function studies in vitro and in vivo suggest it functions as a pivotal switch between physiological and pathological cardiac hypertrophy and may regulate cardiomyocyte proliferation. lncExACT1 appears to work, at least in part, through binding and inhibiting the microRNA, miR-222, which we have previously shown is necessary for physiological cardiac growth and exercise-induced cardiomyogenesis. We propose to extend these studies in three integrated Specific Aims.
In Aim 1, we will comprehensively identify and functionally characterize in cardiomyocytes candidate lncRNAs differentially regulated in exercised hearts in comparison to pressure-overload induced pathological hypertrophy and HF.
In Aim 2, we will characterize the biological roles of lncExACT1 in vivo in exercise and pressure-overload, as well as in a genetic model of dilated cardiomyopathy.
In Aim 3, we will delineate the mechanisms responsible for lncExACT1?s cardiac effects, including binding to miRNAs and proteins as well as local genomic effects on gene expression. Successful completion of the proposed studies will advance our understanding of cardiac hypertrophy and HF, as well as identifying novel pathways and potential therapeutic targets, such as lncExACT1, that can mitigate these clinically important conditions and regulate endogenous cardiomyogenesis.

Public Health Relevance

This proposal focuses on identifying specific RNA molecules that promote healthy growth of the heart and could prevent heart failure. Thus, the proposed research is relevant to public health and the missions of the NIH and NHLBI to develop new fundamental knowledge and to use that knowledge to reduce illness and enhance health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL146464-01A1
Application #
9885953
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2019-12-01
Project End
2023-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114