| Authors |
Kakoki M, Bahnson EM, Hagaman JR, Siletzky RM, Grant R, Kayashima Y, Li F, Lee
EY, Sun MT, Taylor JM, Rice JC, Almeida MF, Bahr BA, Jennette JC, Smithies O,
Maeda-Smithies N
|
| Submitted By |
Nobuyo Maeda on 8/2/2019 |
| Status |
Published |
| Journal |
JCI insight |
| Year |
2019 |
| Date Published |
|
| Volume : Pages |
4 : Not Specified |
| PubMed Reference |
31217360 |
| 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.
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