Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition

Bambang Widyantoro, Noriaki Emoto, Kazuhiko Nakayama, Dyah W. Anggrahini, Suko Adiarto, Naoko Iwasa, Keiko Yagi, Kazuya Miyagawa, Yoshiyuki Rikitake, Takashi Suzuki, Yaz Y. Kisanuki, Masashi Yanagisawa, Ken Ichi Hirata

Research output: Contribution to journalArticle

222 Citations (Scopus)

Abstract

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. METHODS AND RESULTS-: We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1;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;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-β 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.

Original languageEnglish (US)
Pages (from-to)2407-2418
Number of pages12
JournalCirculation
Volume121
Issue number22
DOIs
StatePublished - Jun 8 2010

Fingerprint

Endothelin-1
Fibrosis
Endothelial Cells
Fibroblasts
Diabetes Mellitus
Heart Failure
Diabetic Cardiomyopathies
Myofibrils
Transforming Growth Factors
Gene Silencing
Streptozocin
Superoxides
Vascular Endothelial Growth Factor A
Small Interfering RNA
Extracellular Matrix
Gene Expression
Glucose

Keywords

  • Cardiomyopathy
  • Diabetes mellitus
  • Endothelin
  • Fibrosis
  • Heart failure

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. / Widyantoro, Bambang; Emoto, Noriaki; Nakayama, Kazuhiko; Anggrahini, Dyah W.; Adiarto, Suko; Iwasa, Naoko; Yagi, Keiko; Miyagawa, Kazuya; Rikitake, Yoshiyuki; Suzuki, Takashi; Kisanuki, Yaz Y.; Yanagisawa, Masashi; Hirata, Ken Ichi.

In: Circulation, Vol. 121, No. 22, 08.06.2010, p. 2407-2418.

Research output: Contribution to journalArticle

Widyantoro, B, Emoto, N, Nakayama, K, Anggrahini, DW, Adiarto, S, Iwasa, N, Yagi, K, Miyagawa, K, Rikitake, Y, Suzuki, T, Kisanuki, YY, Yanagisawa, M & Hirata, KI 2010, 'Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition', Circulation, vol. 121, no. 22, pp. 2407-2418. https://doi.org/10.1161/CIRCULATIONAHA.110.938217
Widyantoro, Bambang ; Emoto, Noriaki ; Nakayama, Kazuhiko ; Anggrahini, Dyah W. ; Adiarto, Suko ; Iwasa, Naoko ; Yagi, Keiko ; Miyagawa, Kazuya ; Rikitake, Yoshiyuki ; Suzuki, Takashi ; Kisanuki, Yaz Y. ; Yanagisawa, Masashi ; Hirata, Ken Ichi. / Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. In: Circulation. 2010 ; Vol. 121, No. 22. pp. 2407-2418.
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abstract = "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. METHODS AND RESULTS-: We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1;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;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-β 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.",
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AU - Widyantoro, Bambang

AU - Emoto, Noriaki

AU - Nakayama, Kazuhiko

AU - Anggrahini, Dyah W.

AU - Adiarto, Suko

AU - Iwasa, Naoko

AU - Yagi, Keiko

AU - Miyagawa, Kazuya

AU - Rikitake, Yoshiyuki

AU - Suzuki, Takashi

AU - Kisanuki, Yaz Y.

AU - Yanagisawa, Masashi

AU - Hirata, Ken Ichi

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