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Regulation of Arterial Function by Apelin/APJ Receptor Mechanisms

Award Number: R15HL124338
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Regulation of Arterial Function by Apelin/APJ Receptor Mechanisms - Mechanisms linking obesity and hypertension to ischemic heart disease (IHD) are not clearly understood. Most patients with IHD suffer from atherosclerotic lesions that limit coronary blood flow; however, more than one-third of all patients have no observable obstruction on angiography. The flow-limiting reductions in coronary arterial diameter in such patients are thought to be due to functional abnormalities (i.e. enhanced vasoconstriction; impaired vasodilation). Apelin is formed in adipose tissue and secreted into the circulation where it has multiple effects on blood vessel function, depending on the vascular bed. Activation of the apelin/APJ receptor-signaling pathway has vasodilatory effects in important vascular beds (e.g. pulmonary) and is generally thought to play a protective role in the cardiovascular system. Our long-term goal is to understand the mechanisms by which apelin regulates vasomotor tone in health and disease. Studies from our lab indicate that apelin causes endothelium- and NO-dependent relaxation of healthy coronary arteries. By contrast, in coronary arteries from hypertensive animals we found that apelin failed to cause arterial relaxation and, instead, inhibited endothelium-dependent relaxation to acetylcholine. Our central hypothesis is that the apelin/APJ receptor axis does not provide a protective vasodilator role in the coronary circulation in hypertension, but rather presents a net vasoconstrictor activity in this vascular bed. It is further hypothesized, based on strong preliminary data, that this adverse effect of apelin is due to inhibition of NO production in hypertensive coronary endothelial cells. It is proposed that the apelin-mediated inhibition of NO synthesis in hypertensive coronary arteries is sufficient to functionally impair the arteries and create a local environment that favors vasoconstriction. This is significant, as it would predictably increase the risk of coronary vascular dysfunction in conditions with elevated plasma apelin levels, such as obesity. Two specific aims are designed to investigate our hypotheses: In Aim #1, we will address the hypothesis that the distinction between the effect of apelin in normotensive vs hypertensive coronary arteries is secondary to changes in APJ receptor levels or location within the vessel wall. Quantitative measurements of gene and protein expression, as well as imaging studies to determine the spatial localization of APJ receptors in the coronary arterial wall will be used to accomplish this aim. In Aim #2, a combination of molecular biological, functional, and imaging techniques will be used to identify which signaling pathway(s) coupling APJ receptor activation to NO production is disrupted in hypertensive coronary arteries. The knowledge gained from these studies will have strong positive impact by increasing our understanding of the mechanisms that control coronary vasomotor tone under hypertensive conditions. Such information may provide new targets for therapeutic interventions in patients with IHD, as well as inform potential therapeutic strategies based on improving hemodynamics with apelin and apelin-like APJ receptor agonists already in clinical development.


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 = -$10,120 )
2024	2020	NORTH DAKOTA STATE UNIVERSITY	1301 12TH AVE N	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	000	2	8/6/2024	COMPETING CONTINUATION	-$10,120
														Subtotal = -$10,120

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Cardiovascular Diseases Research	000	2	3/22/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Cardiovascular Diseases Research	000	2	8/12/2022	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $435,000 )
2020	2020	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	000	2	4/20/2020	COMPETING CONTINUATION	$435,000
2020	2015	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	001	1	7/7/2020	NEW	$0
														Subtotal = $435,000

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2015	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Cardiovascular Diseases Research	000	1	2/28/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $435,000 )
2015	2015	NORTH DAKOTA STATE UNIVERSITY	P.O. BOX 5405	FARGO	ND	58105	CASS	USA	Cardiovascular Diseases Research	000	1	3/23/2015	NEW	$435,000
														Subtotal = $435,000

Grand Total All Awards = $859,880

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Regulation of Arterial Function by Apelin/APJ Receptor Mechanisms

Award Number: R15HL124338

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/20/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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