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

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE

Publication: Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: [Dallas, Tex., etc., American Heart Association, etc.]

Insulin Receptor Substrate Proteins*/metabolism ; Insulin Receptor Substrate Proteins*/genetics ; Ryanodine Receptor Calcium Release Channel*/metabolism ; Ryanodine Receptor Calcium Release Channel*/genetics ; Mice, Knockout* ; Arrhythmias, Cardiac*/metabolism ; Arrhythmias, Cardiac*/etiology ; Arrhythmias, Cardiac*/prevention & control ; Arrhythmias, Cardiac*/genetics ; Calcium*/metabolism ; Myocytes, Cardiac*/metabolism ; Homeostasis*; Animals ; Humans ; Mice ; Retrospective Studies ; Male ; Signal Transduction ; Female ; Calcium Signaling ; Middle Aged ; Proto-Oncogene Proteins c-akt/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Adult

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.

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R01 HL130346 United States HL NHLBI NIH HHS; R01 HL127764 United States HL NHLBI NIH HHS; R01 HL157781 United States HL NHLBI NIH HHS; R01 HL108379 United States HL NHLBI NIH HHS; R01 HL157741 United States HL NHLBI NIH HHS; R01 HL112413 United States HL NHLBI NIH HHS

Keywords: arrhythmias, cardiac; calcium; calcium-calmodulin-dependent protein kinase type 2; insulin receptor substrate proteins; ryanodine receptor calcium release channel

0 (Insulin Receptor Substrate Proteins)
0 (Ryanodine Receptor Calcium Release Channel)
SY7Q814VUP (Calcium)
0 (Irs2 protein, mouse)
0 (IRS2 protein, human)
0 (ryanodine receptor 2. mouse)
0 (RyR2 protein, human)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)

Date Created: 20240910 Date Completed: 20241209 Latest Revision: 20241212

20241212

PMC11631690

10.1161/CIRCULATIONAHA.123.065048

39253856