Stress activated signalling impaired protein quality control pathways in human hypertrophic cardiomyopathy

Hassoun, Roua and Budde, Heidi and Zhazykbayeva, Saltanat and Herwig, Melissa and Sieme, Marcel and Delalat, Simin and Mostafi, Nusratul and Gömöri, Kamilla and Tangos, Melina and Jarkas, Muhammad and Pabel, Steffen and Bruckmüller, Stefanie and Skrygan, Marina and Lódi, Mária and Jaquet, Kornelia and Sequeira, Vasco and Gambichler, Thilo and Remedios, Cris Dos and Kovács, Árpád and Mannherz, Hans Georg and Mügge, Andreas and Sossalla, Samuel and Hamdani, Nazha (2021) Stress activated signalling impaired protein quality control pathways in human hypertrophic cardiomyopathy. International Journal of Cardiology, 344. pp.160-169. ISSN 01675273

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Link to published document: http://doi.org/10.1016/j.ijcard.2021.09.009

Abstract

Hypertrophic cardiomyopathy (HCM) is a complex myocardial disorder with no well-established disease-modifying therapy so far. Our study aimed to investigate how autophagy, oxidative stress, inflammation, stress signalling pathways, and apoptosis are hallmark of HCM and their contribution to the cardiac dysfunction. Demembranated cardiomyocytes from patients with HCM display increased titin-based stiffness (Fpassive), which was corrected upon antioxidant treatment. Titin as a main determinant of Fpassive was S-glutathionylated and highly ubiquitinated in HCM patients. This was associated with a shift in the balance of reduced and oxidized forms of glutathione (GSH and GSSG, respectively). Both heat shock proteins (HSP27 and alpha-ss crystalline) were upregulated and S-glutathionylated in HCM. Administration of HSPs in vitro significantly reduced HCM cardiomyocyte stiffness. High levels of the phosphorylated monomeric superoxide anion-generating endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO) bioavailability, decreased soluble guanylyl cyclase (sGC) activity, and high levels of 3-nitrotyrosine were observed in HCM. Many regulators of signal transduction pathways that are involved in autophagy, apoptosis, cardiac contractility, and growth including the mitogen-activated protein kinase (MAPK), protein kinase B (AKT), glycogen synthase kinase 3ss (GSK-3ss), mammalian target of rapamycin (mTOR), forkhead box O transcription factor (FOXO), c-Jun N-terminal protein kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) were modified in HCM. The apoptotic factors cathepsin, procaspase 3, procaspase 9 and caspase 12, but not caspase 9, were elevated in HCM hearts and associated with increased proinflammatory cytokines (Interleukin 6 (IL-6), interleukin 18 (IL-18), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), the Toll-like receptors 2 (TLR2) and the Toll-like receptors 4 (TLR4)) and oxidative stress (3-nitrotyrosine and hydrogen peroxide (H2O2)). Here we reveal stress signalling and impaired PQS as potential mechanisms underlying the HCM phenotype. Our data suggest that reducing oxidative stress can be a viable therapeutic approach to attenuating the severity of cardiac dysfunction in heart failure and potentially in HCM and prevent its progression.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 10 Dec 2021 03:47
Last Modified: 10 Dec 2021 03:47
URI: http://eprints.victorchang.edu.au/id/eprint/1172

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