IRS2 Signaling Protects Against Stress-Induced Arrhythmia by Maintaining Ca 2+ Homeostasis.

Autor:	Shi Q; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Wang J; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Malik H; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Li X; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Streeter J; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Sharafuddin J; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Weatherford E; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Fraternal Order of Eagles Diabetes Research Center (E.W., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Stein D; The Charles Bronfman Institute for Personalized Medicine (D.S., Y.I.), Icahn School of Medicine at Mount Sinai, New York, NY.; Department of Genetics and Genome Sciences (D.S., Y.I.), Icahn School of Medicine at Mount Sinai, New York, NY., Itan Y; The Charles Bronfman Institute for Personalized Medicine (D.S., Y.I.), Icahn School of Medicine at Mount Sinai, New York, NY.; Department of Genetics and Genome Sciences (D.S., Y.I.), Icahn School of Medicine at Mount Sinai, New York, NY., Chen B; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Hall D; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Abboud Cardiovascular Research Center (D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Song LS; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Abboud Cardiovascular Research Center (D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Fraternal Order of Eagles Diabetes Research Center (E.W., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City., Abel ED; Department of Internal Medicine (Q.S., J.W., H.M., X.L., J. Streeter, J. Sharafuddin, E.W., B.C., D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Abboud Cardiovascular Research Center (D.H., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Fraternal Order of Eagles Diabetes Research Center (E.W., L.-S.S., E.D.A.), Carver College of Medicine, University of Iowa, Iowa City.; Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA (E.D.A.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2024 Dec 10; Vol. 150 (24), pp. 1966-1983. Date of Electronic Publication: 2024 Sep 10.
DOI:	10.1161/CIRCULATIONAHA.123.065048
Abstrakt:	Background: The docking protein IRS2 (insulin receptor substrate protein-2) is an important mediator of insulin signaling and may also regulate other signaling pathways. Murine hearts with cardiomyocyte-restricted deletion of Irs2 (cIRS2-KO) are more susceptible to pressure overload-induced cardiac dysfunction, implying a critical protective role of IRS2 in cardiac adaptation to stress through mechanisms that are not fully understood. There is limited evidence regarding the function of IRS2 beyond metabolic homeostasis regulation, particularly in the context of cardiac disease. Methods: A retrospective analysis of an electronic medical record database was conducted to identify patients with IRS2 variants and assess their risk of cardiac arrhythmias. Arrhythmia susceptibility was examined in cIRS2-KO mice. The underlying mechanisms were investigated using confocal calcium imaging of ex vivo whole hearts and isolated cardiomyocytes to assess calcium handling, Western blotting to analyze the involved signaling pathways, and pharmacological and genetic interventions to rescue arrhythmias in cIRS2-KO mice. Results: The retrospective analysis identified patients with IRS2 variants of uncertain significance with a potential association to an increased risk of cardiac arrhythmias compared with matched controls. cIRS2-KO hearts were found to be prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. Confocal calcium imaging of ex vivo whole hearts and single isolated cardiomyocytes from cIRS2-KO hearts revealed decreased Ca²⁺ transient amplitudes, increased spontaneous Ca²⁺ sparks, and reduced sarcoplasmic reticulum Ca²⁺ content during sympathetic stress, indicating sarcoplasmic reticulum dysfunction. We identified that overactivation of the AKT1/NOS3 (nitric oxide synthase 3)/CaMKII (Ca²⁺/calmodulin-dependent protein kinase II)/RyR2 (type 2 ryanodine receptor) signaling pathway led to calcium mishandling and catecholamine-sensitive ventricular tachycardia in cIRS2-KO hearts. Pharmacological AKT inhibition or genetic stabilization of RyR2 rescued catecholamine-sensitive ventricular tachycardia in cIRS2-KO mice. Conclusions: Cardiac IRS2 inhibits sympathetic stress-induced AKT/NOS3/CaMKII/RyR2 overactivation and calcium-dependent arrhythmogenesis. This novel IRS2 signaling axis, essential for maintaining cardiac calcium homeostasis under stress, presents a promising target for developing new antiarrhythmic therapies. Competing Interests: None.
Databáze:	MEDLINE
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