Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition.
BACKGROUND
Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients have been associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and fibroblast recruitment from an as-yet unknown source. The underlying mechanism, however, remains elusive. Here, we hypothesize that ET-1 might contribute to the accumulation of cardiac fibroblasts through an endothelial-to-mesenchymal transition in diabetic hearts.


RESULTS
We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1(f/f);Tie2-Cre (+)] mice and their wild-type littermates using the toxin streptozotocin. Gene expression and histological and functional parameters were examined at 8, 24, and 36 weeks after the induction of diabetes mellitus. Diabetes mellitus increased cardiac ET-1 expression in wild-type mice, leading to mitochondrial disruption and myofibril disarray through the generation of superoxide. Diabetic mice also showed impairment of cardiac microvascularization and a decrease in cardiac vascular endothelial growth factor expression. ET-1 further promotes cardiac fibrosis and heart failure through the accumulation of fibroblasts via endothelial-to-mesenchymal transition. All of these features were abolished in ET-1(f/f);Tie2-Cre (+) hearts. Targeted ET-1 gene silencing by small interfering RNA in cultured human endothelial cells ameliorated high glucose-induced phenotypic transition and acquisition of a fibroblast marker through the inhibition of transforming growth factor-beta signaling activation and preservation of the endothelial cell-to-cell contact regulator VE-cadherin.


CONCLUSIONS
These results provide new insights suggesting that diabetes mellitus-induced cardiac fibrosis is associated with the emergence of fibroblasts from endothelial cells and that this endothelial-to-mesenchymal transition process is stimulated by ET-1. Targeting endothelial cell-derived ET-1 might be beneficial in the prevention of diabetic cardiomyopathy.
Widyantoro
Bambang
B
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Emoto
Noriaki
N
Nakayama
Kazuhiko
K
Anggrahini
Dyah W
DW
Adiarto
Suko
S
Iwasa
Naoko
N
Yagi
Keiko
K
Miyagawa
Kazuya
K
Rikitake
Yoshiyuki
Y
Suzuki
Takashi
T
Kisanuki
Yaz Y
YY
Yanagisawa
Masashi
M
Hirata
Ken-Ichi
K
D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology*; D019332:Endothelin-1 / Q000172:deficiency / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D014471:Umbilical Veins / Q000166:cytology
D019332:Endothelin-1