Heart failure occurs when the cardiac muscle is weakened and cannot pump sufficiently to meet the body's need for blood and oxygen. Heart failure affects approximately 6 million of Americans and becomes a tremendous burden on our healthcare and economy system. Hypertension is one of the most prominent risk factors of heart failure. In response to high blood pressure, ventricular wall stress is augmented to overcome the increase of afterload pressure. The heart then manifests parallel growth to ameliorate wall stress. This concentric hypertrophic growth, once adaptive, may lead to fibrosis, inflammation, cardiac dysfunction and eventually heart failure. Despite the important of this devastating disease, our understanding is incomplete. Multiple events in heart failure progression are potent inducers of the unfolded protein response (UPR), a cellular adaptive process to cope with protein-folding stress. Three signaling transducers participate in the UPR to increase protein-folding capacity, reduce load of protein-folding and degrade terminally misfolded proteins. However, the role of the UPR in pressure overload-induced cardiac hypertrophy and heart failure remains to be defined. Preliminary work shows that Xbp1s, the most conserved branch of the UPR from yeast to mammals, is acutely and potently induced in heart. Overexpression of Xbp1s in cardiomyocyte is sufficient to cause hypertrophy. GFAT1, the rate-limiting enzyme of the hexosamine biosynthetic pathway, is discovered as a novel transcriptional target of Xbp1s. Inducible overexpression of GFAT1 leads to more profound response to pressure overload. GFAT1, and the hexosamine biosynthesis, may therefore mediate Xbp1s-induced hypertrophic growth. Moreover, Xbp1s overexpression leads to strong activation of mTORC1, an essential player in nutrient sensing and cell growth. Xbp1s may therefore couple the UPR, protein-folding, hexosamine biosynthesis and cell growth. Studies proposed here aim to define the role of the Xbp1/GFAT1/mTORC1 axis in cardiac hypertrophy and pathological remodelling in response to pressure overload. Both gain- and loss-of- function approaches using inducible systems will be employed in rodents. Comprehensive analysis for cardiac function, histological changes, and molecular derangements will be conducted. In vivo work will be corroborated by in vitro experiments with isolated neonatal myocytes to further decipher underlying mechanisms. Elucidation of the role of Xbp1s/GFAT1 in cardiac hypertrophy and pathological remodelling will greatly advance our understanding of the pathology of heart failure and pave a way for future clinical applications.

Public Health Relevance

Heart failure, which affects approximate 6 million Americans with 5-year survival of 50%, has been singled out as an epidemic. Hypertension is one of the most important risk factors of heart failure, with underlying mechanisms incompletely understood. Studies laid out here will provide mechanistic link between high blood pressure, heart growth and cellular protein-folding process, which likely provides new insights of our understanding of pathological cardiac remodelling and sheds light on novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL137723-01
Application #
9362022
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$405,000
Indirect Cost
$155,000
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390