Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production.

Abstract

Engulfment and cell motility protein 1 (ELMO1) is part of a guanine nucleotide exchange factor for Ras-related C3 botulinum toxin substrate (Rac), and ELMO1 polymorphisms were identified to be associated with diabetic nephropathy in genome-wide association studies. We generated a set of Akita Ins2C96Y diabetic mice having 5 graded cardiac mRNA levels of ELMO1 from 30% to 200% of normal and found that severe dilated cardiomyopathy develops in ELMO1-hypermorphic mice independent of renal function at age 16 weeks, whereas ELMO1-hypomorphic mice were completely protected. As ELMO1 expression increased, reactive oxygen species indicators, dissociation of the intercalated disc, mitochondrial fragmentation/dysfunction, cleaved caspase-3 levels, and actin polymerization increased in hearts from Akita mice. Cardiomyocyte-specific overexpression in otherwise ELMO1-hypomorphic Akita mice was sufficient to promote cardiomyopathy. Cardiac Rac1 activity was positively correlated with the ELMO1 levels, and oral administration of a pan-Rac inhibitor, EHT1864, partially mitigated cardiomyopathy of the ELMO1 hypermorphs. Disrupting Nox4, a Rac-independent NADPH oxidase, also partially mitigated it. In contrast, a pan-NADPH oxidase inhibitor, VAS3947, markedly prevented cardiomyopathy. Our data demonstrate that in diabetes mellitus ELMO1 is the "rate-limiting" factor of reactive oxygen species production via both Rac-dependent and Rac-independent NADPH oxidases, which in turn trigger cellular signaling cascades toward cardiomyopathy.

• Authors: Masao Kakoki, Edward M Bahnson, John R Hagaman, Robin M Siletzky, Ruriko Grant, Yukako Kayashima, Feng Li, Esther Y Lee, Michelle T Sun, Joan M Taylor, Jessica C Rice, Michael F Almeida, Ben A Bahr, J Charles Jennette, Oliver Smithies, Nobuyo Maeda-Smithies
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 12 (06 20 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31217360 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Connexin 43
• ELMO1 protein, mouse
• GJA1 protein, mouse
• Reactive Oxygen Species
• NADPH Oxidase 4
• Nox4 protein, mouse
• rac GTP-Binding Proteins

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Cell Movement
• Connexin 43 (metabolism)
• Diabetic Cardiomyopathies (etiology, genetics, metabolism, pathology)
• Female
• Heart (physiopathology)
• Male
• Mice
• Mitochondria (metabolism, pathology)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• NADPH Oxidase 4 (metabolism)
• Reactive Oxygen Species (metabolism)
• rac GTP-Binding Proteins (metabolism)