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Regulation of Myocardial Phospholipases and Lipases in Diabetic Myocardium

Award Number: R01HL118639
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Regulation of Myocardial Phospholipases and Lipases in Diabetic Myocardium - ABSTRACT Heart disease is the most common cause of death in industrialized nations. The presence of underlying diabetes is the greatest risk factor for the progression of heart disease. During the current grant interval, we have discovered previously unknown lipid metabolic pathways and signaling molecules which lead to the generation of eicosanoid-lysophospholipids. Remarkably, the vast majority of eicosanoids in myocardium were found to be esterified to the glycerol backbone of lysophospholipids. In addition, induction of Type I diabetes in wild-type mice or ischemic damage in isolated wild-type mouse hearts resulted in dramatic increases in pro-inflammatory eicosanoid-lysophospholipids. This new class of phospholipids serve as inflammatory mediators by inducing the release of TNFa from monocytes or macrophages. Importantly, genetic ablation of iPLA2g (PNPLA8) substantially decreased the levels of eicosanoid-lysophospholipids in myocardium in the diabetic state, during myocardial ischemia and synergistically decreased their synthesis in diabetic myocardium rendered ischemic. Accordingly, we propose that iPLA2g plays a central role in the pathophysiologic development of diabetic heart disease and promotes the lethal sequelae of diabetic cardiomyopathy. In Specific Aim 1, we will utilize stable isotope labeling of isolated perfused mouse hearts from genetically engineered cardiac myocyte-specific conditional iPLA2g knockout mice we have generated. These studies will investigate the roles of iPLA2g in the metabolic flux of: 1) non-esterified and esterified eicosanoids; 2) eicosanoid-lysophospholipids; and 3) other salient oxidized phospholipids. Stable isotope pulse-chase experiments followed by penetrating bioinformatic analyses will determine rates of metabolic flux through these newly discovered pathways. Translationally, we will explore the impact of Type 2 diabetes on myocardial ischemic damage and the potential salvage of ischemic myocardium in cardiac myocyte-specific iPLA2g KO mice we engineered. Endpoints of analysis include infarct size, hemodynamic performance, and post-translational modifications of iPLA2g. In Specific Aim 2, we will utilize cardiac myocyte-specific iPLA2b KO mice we have generated to explore the role of iPLA2b in promoting myocardial ischemic damage and arrhythmias in WT vs. iPLA2b KO mice in the context of Type II diabetes. Next, we will determine the ability of iPLA2b to catalyze acyltransferase or transacylase mediated re-esterification of eicosanoid-lysophospholipids to generate oxidized phospholipids which have been implicated in damage associated molecular patterns. In Specific Aim 3, the mechanisms through which a high fat diet induces eicosanoid-lysolipid synthesis accompanied by inflammation and mitochondrial dysfunction will be studied. The roles of lysophospholipases in modulating eicosanoid-lysophospholipid levels and activation mechanisms for iPLA2g will be examined. Collectively, the proposed studies will establish the significance of iPLA2g and iPLA2b in mediating the newly identified pathways of eicosanoid-lysophospholipid synthesis and metabolism and determine their impact on diabetic cardiomyopathy and acute ischemic damage in diabetic hearts.


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 = $698,060 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	12	2/27/2025	NON-COMPETING CONTINUATION	$698,060
														Subtotal = $698,060

Issue Date FY: 2024 ( Subtotal = $760,109 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	001	11	6/21/2024	NON-COMPETING CONTINUATION	$62,049
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	11	1/12/2024	NON-COMPETING CONTINUATION	$698,060
														Subtotal = $760,109

Issue Date FY: 2023 ( Subtotal = $779,778 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	10	2/6/2023	NON-COMPETING CONTINUATION	$779,778
														Subtotal = $779,778

Issue Date FY: 2022 ( Subtotal = $785,597 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	003	9	6/30/2022	COMPETING CONTINUATION	$279
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	9	1/14/2022	COMPETING CONTINUATION	$785,597
2022	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	002	8	6/30/2022	NON-COMPETING CONTINUATION	-$279
2022	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	8	1/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $785,597

Issue Date FY: 2020 ( Subtotal = $762,405 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	8	7/22/2020	NON-COMPETING CONTINUATION	$762,405
														Subtotal = $762,405

Issue Date FY: 2019 ( Subtotal = $762,405 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	7	5/26/2019	NON-COMPETING CONTINUATION	$762,405
														Subtotal = $762,405

Issue Date FY: 2018 ( Subtotal = $762,405 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	6	5/21/2018	NON-COMPETING CONTINUATION	$762,405
														Subtotal = $762,405

Issue Date FY: 2017 ( Subtotal = $762,405 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	002	5	9/28/2017	COMPETING CONTINUATION	$101,510
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	5	3/30/2017	COMPETING CONTINUATION	$762,405
2017	2016	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	4	9/28/2017	EXTENSION WITH OR WITHOUT FUNDS	-$101,510
														Subtotal = $762,405

Issue Date FY: 2016 ( Subtotal = $755,397 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	4	5/31/2016	EXTENSION WITH OR WITHOUT FUNDS	$755,397
														Subtotal = $755,397

Issue Date FY: 2015 ( Subtotal = $744,066 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	3	5/8/2015	NON-COMPETING CONTINUATION	$744,066
														Subtotal = $744,066

Issue Date FY: 2014 ( Subtotal = $740,290 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	2	5/12/2014	NON-COMPETING CONTINUATION	$740,290
														Subtotal = $740,290

Issue Date FY: 2013 ( Subtotal = $719,138 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	1	5/24/2013	NEW	$719,138
														Subtotal = $719,138

Grand Total All Awards = $9,032,055

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Regulation of Myocardial Phospholipases and Lipases in Diabetic Myocardium

Award Number: R01HL118639

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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