CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia

Chih Yuan Lin, Yu Juei Hsu, Shih Che Hsu, Ying Chen, Herng Sheng Lee, Shih Hua Lin, Shih Ming Huang, Chien Sung Tsai, Chun Che Shih

Research output: Contribution to journalArticle

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Abstract

Cannabinoid receptor type 1 (CB1R) plays an important role in the development of myocardial hypertrophy and fibrosis-2 pathological features of uremic cardiomyopathy. However, it remains unknown whether CB1R is involved in the pathogenesis of uremic cardiomyopathy. Here, we aimed to elucidate the role of CB1R in the development of uremic cardiomyopathy via modulation of Akt signalling. The heart size and myocardial fibrosis were evaluated by echocardiography and immunohistochemical staining, respectively, in 5/6 nephrectomy chronic kidney disease (CKD) mice treated with a CB1R antagonist. CB1R and fibrosis marker expression levels were determined by immunoblotting in H9c2 cells exposed to the uremic toxin indoxyl sulfate (IS), with an organic anion transporter 1 inhibitor or a CB1R antagonist or agonist. Akt phosphorylation was also assessed to examine the signaling pathways downstream of CB1R activation induced by IS in H9c2 cells. CKD mice exhibited marked left ventricular hypertrophy and myocardial fibrosis, which were reversed by treatment with the CB1R antagonist. CB1R, collagen I, transforming growth factor (TGF)-β, and α-smooth muscle actin (SMA) expression showed time- and dose-dependent upregulation in H9c2 cells treated with IS. The inhibition of CB1R by either CB1R antagonist or small interfering RNA-mediated knockdown attenuated the expression of collagen I, TGF-β, and α-SMA in IS-treated H9c2 cells, while Akt phosphorylation was enhanced by CB1R agonist and abrogated by CB1R antagonist in these cells. In summary, we conclude that CB1R blockade attenuates LVH and Akt-mediated cardiac fibrosis in a CKD mouse model. Uremic toxin IS stimulates the expression of CB1R and fibrotic markers and CB1R inhibition exerts anti-fibrotic effects via modulation of Akt signaling in H9c2 myofibroblasts. Therefore, the development of drugs targeting CB1R may have therapeutic potential in the treatment of uremic cardiomyopathy.

Original languageEnglish
Pages (from-to)249-261
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume85
DOIs
Publication statusPublished - Aug 1 2015
Externally publishedYes

Fingerprint

Indican
Cannabinoid Receptor Antagonists
Uremia
Left Ventricular Hypertrophy
Fibrosis
Cardiomyopathies
Chronic Renal Insufficiency
Transforming Growth Factors
Smooth Muscle
Actins
Collagen
Phosphorylation
Organic Anion Transporters
Cannabinoid Receptors
Myofibroblasts
Drug Delivery Systems
Nephrectomy
Immunoblotting
Hypertrophy
Small Interfering RNA

Keywords

  • Akt
  • Chronic kidney disease
  • Fibrosis
  • Left ventricular hypertrophy
  • Uremic cardiomyopathy

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia. / Lin, Chih Yuan; Hsu, Yu Juei; Hsu, Shih Che; Chen, Ying; Lee, Herng Sheng; Lin, Shih Hua; Huang, Shih Ming; Tsai, Chien Sung; Shih, Chun Che.

In: Journal of Molecular and Cellular Cardiology, Vol. 85, 01.08.2015, p. 249-261.

Research output: Contribution to journalArticle

Lin, Chih Yuan ; Hsu, Yu Juei ; Hsu, Shih Che ; Chen, Ying ; Lee, Herng Sheng ; Lin, Shih Hua ; Huang, Shih Ming ; Tsai, Chien Sung ; Shih, Chun Che. / CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 85. pp. 249-261.
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AU - Lee, Herng Sheng

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AU - Huang, Shih Ming

AU - Tsai, Chien Sung

AU - Shih, Chun Che

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