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- W2883662274 abstract "Abnormal left ventricular (LV) relaxation and increased diastolic stiffness are important features of heart failure with preserved ejection fraction (HFpEF); the 2 major contributors to LV diastolic function are the cardiomyocytes and the extracellular matrix.1 Cardiomyocytes govern LV relaxation and are a determinant of LV chamber distensibility. Increased cardiomyocyte stiffness can be caused by sarcomeric myofilaments; the focus of the work by Hopf et al2 is on the role of the myofilament titin, a major contributor to diastolic stiffening in HFpEF.3,4 Approximately 1/3 of HFpEF patients have diabetes mellitus (DM), and Hopf et al2 provide important insights in the insulin-related signaling pathways that modify titin’s stiffness in HFpEF patients with DM.Article, see p 342 The extensible I-band region of titin comprises (1) tandem immunoglobulins segments, (2) the PEVK (proline-glutamic acid-valine-lysine-rich element), and (3) the N2B-Us (a unique sequence [Us] that is part of the N2B element).5 Titin’s stiffness can be modulated through differential mRNA splicing that gives rise to stiff and compliant titin isoforms.6 Upregulation of compliant isoforms occurs in pathological conditions, presumably to counteract fibrosis.7 Upregulating compliant titin can be experimentally accomplished by targeting RBM20 (RNA-binding motif protein 20), and this normalizes titin’s stiffness in models with diastolic dysfunction.8,9 Posttranslational modification of titin also alters titin’s stiffness.10 S4010 and S4099 in N2B-Us can be phosphorylated, resulting in a reduction of titin stiffness, whereas phosphorylation of the S11878 and S12022, located in the PEVK segment, results in increased stiffness.Previous studies have shown that increased cardiomyocyte stiffness in DM is a consequence of deranged titin phosphorylation, but the pathways connecting insulin deficiency to altered titin phosphorylation have not been established. Hopf et al2 shed light on the signaling pathways involved and, importantly, provide potential therapeutic …" @default.
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- W2883662274 date "2018-07-20" @default.
- W2883662274 modified "2023-10-05" @default.
- W2883662274 title "Softening the Stressed Giant Titin in Diabetes Mellitus" @default.
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- W2883662274 doi "https://doi.org/10.1161/circresaha.118.313396" @default.
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