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Enhancer of zeste homolog 2-mediated epigenetic activation of acid sphingomyelinase in endothelial dysfunction during obesity

Award Number: R01HL150007
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Endothelial dysfunction is an early defect in obesity, which is a major contributor to increased cardiovascular morbidity and mortality such as arterial stiffness, atherosclerosis, and hypertension. Recent studies have demonstrated a critical role of acid sphingomyelinase (ASM)-ceramide signaling in instigation of Nlrp3 inflammasomes and endothelial dysfunction during obesity and diabetes. The present proposal seeks to explore a novel mechanism mediating transcriptional control of ASM gene expression in ECs and determine how dysregulated ASM expression and activity promote vascular injury in obesity. Enhancer of zeste homolog 2 (Ezh2) is a histone methyltransferase that normally suppresses methylated genes, serving as a crucial epigenetic regulatory mechanism in gene expression. In preliminary studies, we found that loss of Ezh2 function increased ASM expression and ceramide levels in the intima leading to neointimal lesions in the carotid arteries of mice fed high fat diet (HFD). Such Ezh2-mediated suppression of ASM gene expression and ceramide signaling were also confirmed in cultured ECs. Based on these observations, we propose a hypothesis that loss of endothelial Ezh2 function upregulates ASM gene expression and augments ceramide production under hyperlipidemic conditions, which trigger Nlrp3 inflammasome activation and produce endothelial injury resulting in subsequent neointimal lesions on the carotid arterial wall. To test this hypothesis, the following Specific Aims are proposed. Specific Aim 1 will determine whether endothelial ASM activation due to loss of Ezh2 function contributes to endothelial dysfunction or injury at the early stage of obesity using endothelium-specific Ezh2 knockout mice (Ezh2ecKO) and their wild type littermates. Specific Aim 2 attempts to test how Ezh2-regulated ASM activation leads to endothelial dysfunction or injury by studying the role of ceramide and ceramide-enriched membrane rafts, Nlrp3 inflammasome activation, pyroptosis, endothelium- dependent vasodilation, inter-endothelial junction disruption, and adaptive endothelial progenitor cell landing or differentiation. In Specific Aim 3, we will explore the molecular mechanisms by which loss of Ezh2 function activates ASM with a main focus on the roles of histone and DNA methylation in cultured ECs from Ezh2ecKO mice and their wild type littermates. The findings will provide new insights into the pathogenesis of endothelial dysfunction and identify Ezh2-ASM pathway as therapeutic target for prevention or treatment of vaculopathy associated with obesity.


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: 2024 ( Subtotal = $438,177 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Cardiovascular Diseases Research	000	5	7/23/2024	NON-COMPETING CONTINUATION	$438,177
														Subtotal = $438,177

Issue Date FY: 2023 ( Subtotal = $447,120 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Cardiovascular Diseases Research	000	4	7/1/2023	NON-COMPETING CONTINUATION	$447,120
														Subtotal = $447,120

Issue Date FY: 2022 ( Subtotal = $447,120 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	000	3	7/13/2022	NON-COMPETING CONTINUATION	$447,120
														Subtotal = $447,120

Issue Date FY: 2021 ( Subtotal = $447,120 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	000	2	7/2/2021	NON-COMPETING CONTINUATION	$447,120
														Subtotal = $447,120

Issue Date FY: 2020 ( Subtotal = $447,120 )
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Cardiovascular Diseases Research	000	1	6/22/2020	NEW	$447,120
														Subtotal = $447,120

Grand Total All Awards = $2,226,657

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Enhancer of zeste homolog 2-mediated epigenetic activation of acid sphingomyelinase in endothelial dysfunction during obesity

Award Number: R01HL150007

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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