Loescher, Christine M. and Breitkreuz, Martin and Li, Yong and Nickel, Alexander and Unger, Andreas and Dietl, Alexander and Schmidt, Andreas and Mohamed, Belal A. and Koetter, Sebastian and Schmitt, Joachim P. and Krueger, Marcus and Kruger, Martina and Toischer, Karl and Maack, Christoph and Leichert, Lars and Hamdani, Nazha and Linke, Wolfgang A. (2020) Regulation of titin-based cardiac stiffness by unfolded domain oxidation (UnDOx). PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 117 (39). pp. 24545-24556. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)Abstract
The relationship between oxidative stress and cardiac stiffness is thought to involve modifications to the giant muscle protein titin, which in turn can determine the progression of heart disease. In vitro studies have shown that S-glutathionylation and disulfide bonding of titin fragments could alter the elastic properties of titin; however, whether and where titin becomes oxidized in vivo is less certain. Here we demonstrate, using multiple models of oxidative stress in conjunction with mechanical loading, that immunoglobulin domains preferentially from the distal titin spring region become oxidized in vivo through the mechanism of unfolded domain oxidation (UnDOx). Via oxidation type-specific modification of titin, UnDOx modulates human cardiomyocyte passive force bidirectionally. UnDOx also enhances titin phosphorylation and, importantly, promotes nonconstitutive folding and aggregation of unfolded domains. We propose a mechanism whereby UnDOx enables the controlled homotypic interactions within the distal titin spring to stabilize this segment and regulate myocardial passive stiffness.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | S-GLUTATHIONYLATION; STRESS; AGGREGATION; MODULATION; ELASTICITY; PREDICTION; PROTEINS; SITES; oxidative stress; myocardial stiffness; single-molecule measurements; proteomics; mechanics |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2021 05:22 |
| Last Modified: | 15 Mar 2021 05:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43742 |
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