The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.

Abstract

The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild-type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca2+ ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction.

• Authors: Karen M O'Shea, Radha Ananthakrishnan, Qing Li, Nosirudeen Quadri, Devi Thiagarajan, Gopalkrishna Sreejit, Lingjie Wang, Hylde Zirpoli, Juan Francisco Aranda, Arthur S Alberts, Ann Marie Schmidt, Ravichandran Ramasamy
• Journal: EBioMedicine (EBioMedicine) Vol. 26 Pg. 165-174 (Dec 2017) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 29239839 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• DIAPH1 protein, human
• Formins
• Sodium-Calcium Exchanger
• Sarcoplasmic Reticulum Calcium-Transporting ATPases

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Cell Line
• Disease Models, Animal
• Formins
• Gene Expression Regulation
• Humans
• Mice
• Myocardial Reperfusion Injury (genetics, physiopathology)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (genetics)
• Signal Transduction (genetics)
• Sodium-Calcium Exchanger (genetics)