Monday, June 30, 2025 6/30/2025

Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury

Award Number: R01HL146514
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury - SUMMARY Sarcolemmal ATP-sensitive K+ (KATP) channels are abundantly expressed in the heart. Several groups have now identified a key role for these channels in mediating cardioprotection against ischemic injury and their participation in the protective mechanism of ischemic preconditioning. In the heart there several different subtypes of KATP channels and little is known about the roles during ischemia and reperfusion. Of particular interest are the KATP channel subtypes present in the coronary smooth muscle (SM) and coronary endothelial cells (EC). There is increasing focus on these coronary channels as a target for blood flow regulation and cardioprotection, yet they are relatively poorly understood. The SM and EC KATP channels are distinct from ventricular KATP channels and they are also distinct from each other. A major barrier to our understanding of their respective roles during a complex event such as myocardial ischemia is the lack of currently available resources specifically to study these two channel subtypes. We have generated novel genetic mouse models that can distinguish these subtypes of KATP channels and show with one of these that EC KATP channels strongly participate in myocardial protection during ischemia/reperfusion. The goal of the proposed studies is systematically to examine the role(s) of the EC and SM KATP channel subtypes in the regulation of coronary blood flow, protection during ischemia and the protective response to ischemic preconditioning. We hypothesize that both EC and SM KATP channel subtypes contribute to the regulation of coronary blood flow and cardioprotection, but through distinctly different mechanisms. Using novel and validated conditional knockout mice, we will specifically target EC or SM KATP channel subtypes. The proposed studies have three Aims. In Aim 1, we will investigate the roles of these two coronary KATP channel subtypes in blood flow during ischemia. We will use isolated, pressurized microvessels and isolated, perfused hearts under normal, hypoxic and ischemic conditions. We will additionally investigate the role of EC and SM KATP channels in the myocardial “no-reflow” phenomenon. Aim 2 will investigate the roles of EC and SM KATP channels in myocardial protection using an in vivo murine I/R model and investigate pathways that regulate infarct development. Aim 3 will investigate the contribution of EC and SM KATP channel subtypes during ischemic preconditioning using an in vivo murine I/R model and cellular assays. We will also examine trafficking of these KATP channel subtypes as a potential protective mechanism and investigate molecular signaling pathways involved. This multi-investigator proposal combines the expertise of three highly established investigators; Dr. Lefer’s extensive expertise with in vivo cardiac ischemia/reperfusion models, and Dr. Coetzee’s track record of studying KATP channels with electrophysiological, biochemical and molecular approaches and Dr. Tinker’s expertise in studying molecular signaling pathways in vascular KATP channels. The proposed studies will provide important molecular insights into the unique functions of coronary KATP channel subtypes under pathophysiological conditions.


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 = -$50,589 )
2025	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	5	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$50,589
														Subtotal = -$50,589

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	001	5	1/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,325
2024	2022	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	3	1/22/2024	NON-COMPETING CONTINUATION	-$373,325
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $732,803 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	4	2/3/2023	NON-COMPETING CONTINUATION	$732,803
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	001	4	8/16/2023	NON-COMPETING CONTINUATION	-$732,803
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	002	5	8/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$732,803
														Subtotal = $732,803

Issue Date FY: 2022 ( Subtotal = $732,803 )
2022	2022	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	3	12/9/2021	NON-COMPETING CONTINUATION	$659,522
2022	2022	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	001	3	6/8/2022	NON-COMPETING CONTINUATION	$73,281
														Subtotal = $732,803

Issue Date FY: 2021 ( Subtotal = $732,803 )
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	2	11/30/2020	NON-COMPETING CONTINUATION	$659,522
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$73,281
														Subtotal = $732,803

Issue Date FY: 2020 ( Subtotal = $756,303 )
2020	2020	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	1	11/29/2019	NEW	$756,303
														Subtotal = $756,303

Grand Total All Awards = $2,904,123

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Roles of Endothelial and Smooth Muscle KATP Channels in Myocardial Ischemic Injury

Award Number: R01HL146514

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/17/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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