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The role of S-glutathione in regulating cardiac myosin binding protein-C function

Award Number: F32HL170509
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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The role of S-glutathione in regulating cardiac myosin binding protein-C function - Project Summary Increased oxidative stress is associated with cardiac cell dysfunction in heart disease. An unbalanced redox state leads to an increase in the post-translational modification of S-Glutathione, which modifies cysteine residues on key myofilament proteins, such as cardiac myosin binding protein-C (cMyBP-C). cMyBP-C regulates contraction and relaxation of the sarcomere. The phosphorylation of cMyBP-C by Protein Kinase A (PKA) is cardioprotective. Yet, in the failing heart, phosphorylation levels of cMyBP-C are reduced, contrary to an increase in S-glutathionylated cMyBP-C. When cardiomyocytes were incubated with oxidized glutathione (GSSG), myofilament calcium sensitivity increased and cross-bridge kinetics slowed. Prior experiments were unable to isolate the specific effects of S-glutathionylated cMyBP-C (i.e., without the effects of other S- glutathionylated proteins) nor the specific sites responsible for the functional change. Phosphorylation and S- glutathionylation of cMyBP-C may have antagonistic effects. Incubating three N’-terminal domains of cMyBP-C with GSSG led to a significant increase in S-glutathionylated cMyBP-C and a downregulation in cMyBP-C phosphorylation. These results indicate that the decrease in cMyBP-C phosphorylation and consequent loss of the cardioprotective effect of phosphorylated cMyBP-C seen in the failing heart could be due to an increase in S-glutathionylated cMyBP-C. In addition, the anti-ischemic drug, ranolazine, has been shown to improve diastolic function to sham levels, which correlated with S-glutathionylated cMyBP-C. These data indicate that a currently available cardiac therapy might be useful in moderating the levels of cMyBP-C S-glutathionylation. Thus, this proposal will identify how the interaction between phosphorylation and S-glutathionylation affects cardiomyocyte function under normal, elevated, and therapeutically treated conditions using our novel “cut and paste” SpyC3 mouse model. Protein domains C0C7 of cMyBP-C will be “cut” from the sarcomere using the tobacco etch viral protease and, after washing steps, recombinant C0C7sc protein with and without modified cysteine residues will replace its location within its endogenous location in the sarcomere. Site-directed mutagenesis will be used to generate cysteine substitution constructs preventing S-glutathionylation at specific residues and the functional effects of each construct will be measured using the “cut and paste” model. Dual incubation of PKA and GSSG with and without ranolazine treatment will determine the functional effects of this interaction. A combination of ProQ Diamond staining, immunoblotting, Phos-tag gels, and mass spectrometry will be used to measure total modification levels and identify the site-specific modifications. Results from this proposal will be the first to identify the functional effects of individual cMyBP-C S-glutathionylated residues and of phosphorylation and S-glutathionylation cMyBP-C crosstalk. This research proposal will lead to a better understanding of the effects of oxidative stress on cMyBP-C function, its potential to affect phosphorylation in the heart, and if a currently available therapeutic might benefit hearts affected by oxidative stress.


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 = -$6,007 )
2026	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	4	8/27/2026	NON-COMPETING CONTINUATION	-$5,470
2026	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	2	7/23/2026	NON-COMPETING CONTINUATION	-$537
														Subtotal = -$6,007

Issue Date FY: 2025 ( Subtotal = $78,040 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	002	4	9/2/2025	NON-COMPETING CONTINUATION	$78,040
2025	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	3	11/27/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$65,207
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	2	11/26/2024	NON-COMPETING CONTINUATION	-$65,207
														Subtotal = $78,040

Issue Date FY: 2024 ( Subtotal = $74,284 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	2	8/26/2024	NON-COMPETING CONTINUATION	$74,284
														Subtotal = $74,284

Issue Date FY: 2023 ( Subtotal = $69,080 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	1	8/18/2023	NEW	$69,080
														Subtotal = $69,080

Grand Total All Awards = $215,397

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The role of S-glutathione in regulating cardiac myosin binding protein-C function

Award Number: F32HL170509

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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