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

Stefanie Bruckmüller, Nazha Hamdani, Samuel Sossalla, Andreas Mügge, Hans Georg Mannherz, Árpád Kovács, Cris Dos Remedios, Thilo Gambichler, Vasco Sequeira, Kornelia Jaquet, Mária Lódi, Marina Skrygan, Roua Hassoun, Steffen Pabel, Muhammad Jarkas, Melina Tangos, Kamilla Gömöri, Nusratul Mostafi, Simin Delalat, Marcel Sieme, Melissa Herwig, Saltanat Zhazykbayeva, Heidi Budde

Journal: International journal of cardiology 2021;344():160-169

PMID: 34517018

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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 (F), which was corrected upon antioxidant treatment. Titin as a main determinant of F 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 α-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 (HO)). 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.

Address: Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany. Electronic address: [email protected].; Department of Dermatology, Skin Cancer Center, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Department of Dermatology, Skin Cancer Center, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Germany. Electronic address: [email protected].; Department of Dermatology, Skin Cancer Center, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Molecular Biophysics, Victor Chang Cardiac Research Institute, Faculty of Medicine and Health, Darlinghurst, Australia. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Anatomy and Molecular Embryology, Ruhr University, Bochum, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].; Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany; Clinic for Cardiology & Pneumology, Georg-August University Goettingen, and DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany. Electronic address: [email protected].; Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany; Department of Cardiology, St. Josef-Hospital and Bergmannsheil, Ruhr University Bochum, Bochum, Germany. Electronic address: [email protected].

DOI: 10.1016/j.ijcard.2021.09.009