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Arrestin domain-containing protein 4 as a novel regulator of glucose metabolism in the ischemic heart

Award Number: R01HL166620
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Arrestin domain-containing protein 4 as a novel regulator of glucose metabolism in the ischemic heart - ABSTRACT The complexity of cardiomyocyte signaling requires scaffolding proteins to coordinate the cellular processes driven by receptors and transporters. β-Arrestins are prototypical intracellular scaffold proteins that negatively regulate cardiac β-adrenergic receptor function via desensitization. Recently, a larger and more ancient family of structurally related arrestins, termed α-arrestins, has been identified, which shares functions in regulating transporter trafficking. Txnip, the best-studied member of α-arrestins, serves as an adaptor protein to facilitate endocytosis of glucose transporters (GLUTs) and suppresses glucose influx through its arrestin domains. We previously found that targeted deletion of Txnip leads to a substantial metabolic switch, directing cardiomyocytes toward enhanced glycolytic metabolism under severe ischemia. Despite the potential to identify new molecular mechanisms, the functions of other α-arrestins, Arrestin domain-containing protein (Arrdc) 1-5, remain largely undefined in the heart. Here we present preliminary data demonstrating that two α- arrestins Arrdc4 and Txnip are related to their conserved arrestin domains and share the function to inhibit GLUT1. Interestingly, this metabolic inhibition was more potent in Arrdc4 than in Txnip. Using our recently- generated Arrdc4 knockout mouse model, the data reveal exciting findings that inhibition of Arrdc4 enhances myocardial glucose uptake during hypoxia and improves outcomes after myocardial infarction. These results define the outlines of an Arrdc4-GLUT1 pathway that may provide a link between cardiac glucose metabolism and cardiomyocyte survival. This project aims to delineate the molecular nature of this pathway and tests its role in the pathogenesis of ischemic heart disease. Aim 1 tests three non-exclusive hypotheses by which Arrdc4 regulates GLUT1 function in cardiomyocytes: (a) specific arrestin domains of Arrdc4 mediate clathrin- dependent endocytosis of GLUT1; (b) Arrdc4 promotes GLUT1 ubiquitination through an E3 ligase-mediated pathway; (c) Arrdc4 and Txnip are complementary in the regulation of cardiomyocyte glucose metabolism. Aim 2 employs the Arrdc4 knockout mouse model to test the overall significance of cardioprotection against myocardial ischemia through a GLUT1-mediated mechanism in vivo. By genetically “reconstituting” the hearts of Arrdc4 knockout mice with the informative Arrdc4 mutant, this aim also tests the roles of the specific molecular mechanisms linking Arrdc4 and GLUT1 in ischemic heart disease. Furthermore, using a combination of virtual screening and cell-based assays, Aim 3 will search for the possible Arrdc4-GLUT1 interaction inhibitors that may improve energy homeostasis and enhance cardiomyocyte survival under hypoxia. These studies are highly innovative as we propose a pathway that has never been entertained as a cardiac metabolic regulator. The resulting knowledge will provide a novel mechanistic basis for understanding the defense mechanism to protect cardiomyocytes against metabolically-challenging environments under ischemia. Thus, we believe that the mechanism of action of Arrdc4 will give new and relevant insights into therapeutic strategy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $392,500 )
2025	2025	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Cardiovascular Diseases Research	000	3	8/6/2025	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $384,650 )
2024	2024	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Cardiovascular Diseases Research	000	2	7/5/2024	NON-COMPETING CONTINUATION	$384,650
														Subtotal = $384,650

Issue Date FY: 2023 ( Subtotal = $392,500 )
2023	2023	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Cardiovascular Diseases Research	000	1	6/5/2023	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $1,169,650

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Arrestin domain-containing protein 4 as a novel regulator of glucose metabolism in the ischemic heart

Award Number: R01HL166620

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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