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Hyperglycemia-induced regulatory mechanism of ER stress by arresting domain-containing protein 4 in diabetic cardiomyopathy

Award Number: R01HL168191
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Hyperglycemia-induced regulatory mechanism of ER stress by arresting domain-containing protein 4 in diabetic cardiomyopathy - ABSTRACT The endoplasmic reticulum (ER) is an organelle that houses factors that assist proteins in their folding and supports the formation of stabilizing covalent modifications. Perturbation of ER functions results in evolutionarily conserved cell stress, the unfolded protein response (UPR). Recent studies have indicated the critical role of ER stress in diabetes-induced cardiac cell death. However, a pathway connecting hyperglycemia to downstream events of UPR has remained elusive. Here, we present preliminary data demonstrating that Arrestin Domain-Containing protein 4 (Arrdc4) is a glucose-responsive protein that mediates ER stress and cardiac dysfunction in diabetes mellitus. Arrdc4 is a member of the ancient family of arrestin-fold proteins with conserved roles in regulating nutrient transporter trafficking as adaptor proteins. We have found that Arrdc4 expression is robustly upregulated by high glucose in cardiomyocytes. Arrdc4 binds to the basal glucose transporter 1 (GLUT1), induces its endocytosis, and blocks cellular glucose uptake. Arrdc4-mediated glucose deprivation leads to the activation of UPR in cardiomyocytes, revealing a unique function of Arrdc4 in cardiomyocyte metabolism and survival. To define the in vivo function of Arrdc4, we generated and characterized a systemic Arrdc4-knockout (KO) mouse model. In this animal model, Arrdc4-KO mice have fasting hypoglycemia, and Arrdc4-KO hearts exhibit a robust increase in myocardial glucose uptake without insulin stimulation. Furthermore, deletion of Arrdc4 reduces ER stress during the development of diabetic cardiomyopathy and protects the heart against cardiomyocyte apoptosis in type 1 diabetes. These results define the outlines of an Arrdc4-GLUT1-UPR pathway that provides a strong link between hyperglycemia and cardiomyocyte survival. This project aims to delineate the molecular nature of this pathway and tests its role in the pathogenesis of diabetic cardiomyopathy. Aim 1 will test three non-exclusive hypotheses by which high glucose induces ER stress: (a) Arrdc4 is a target of the glucose-sensing transcriptional mechanism, (b) Arrdc4 sensitizes cardiomyocytes to ER stress by energy insufficiency through GLUT1 inhibition, and (c) Arrdc4 may even promote ER stress through a mechanism beyond GLUT1 interaction. Aim 2a will characterize the cardiac metabolic phenotype in the type 2 diabetic model to determine whether Arrdc4-KO mouse hearts are protected from proteotoxic apoptosis. Moreover, Aim 2b will test the hypothesis that the beneficial effect of Arrdc4 deficiency in diabetes is cardiac autonomous or secondary to the glycemic control by skeletal muscle using our newly-generated inducible, tissue-specific Arrdc4-KO mice, focusing on the significance of Arrdc4 in exercise intolerance, an independent predictor of poor prognosis in diabetes. These studies are highly innovative as we propose a pathway that has never been entertained as a cardiac stress regulator in diabetes. The resulting knowledge will provide a new mechanistic basis for understanding the defense mechanism to protect cardiomyocytes against diabetic insults. Based on the novelty of the study, this application is highly significant.


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: 2026 ( Subtotal = $392,500 )
2026	2026	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Cardiovascular Diseases Research	000	3	2/23/2026	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

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	2	1/2/2025	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $392,500 )
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	1	1/9/2024	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $1,177,500

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Hyperglycemia-induced regulatory mechanism of ER stress by arresting domain-containing protein 4 in diabetic cardiomyopathy

Award Number: R01HL168191

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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