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Levosimendan inhibits interleukin-1β-induced apoptosis through activation of Akt and inhibition of inducible nitric oxide synthase in rat cardiac fibroblasts.
Eur J Pharmacol. 2015 Dec 15; 769:86-92.EJ

Abstract

Levosimendan, a calcium sensitizer, known as an inotropic agent has a cytoprotective effect against apoptosis in cardiomyocytes. However, the cytoprotective effect of levosimendan on cardiac fibroblasts has not been clarified. The aim of this study was to examine whether levosimendan modulates interleukin (IL)-1β-induced apoptosis in adult rat cardiac fibroblast. Cardiac fibroblasts were isolated from adult male Wistar rats. Apoptosis of cardiac fibroblasts was evaluated by 4',6-diamidino-2-phenylindole staining and TdT-mediated d-UTP nick end labeling (TUNEL)-based staining. Expression of inducible nitric oxide (NO) synthase (iNOS) and phosphorylation of Akt (Ser473) were determined by Western blotting. Assessment of NO production in the culture medium was performed by using 4,5-diaminofluorescein as a fluorescent probe. Immunofluorescence staining was performed to examine cytochrome-c translocation. Levosimendan (3-100μM) concentration-dependently inhibited IL-1β (4ng/ml, 24h)-induced apoptotic changes in cardiac fibroblasts, such as cellular shrinkage, nuclear condensation and the increase of TUNEL-positive cells. Levosimendan inhibited IL-1β-induced iNOS expression and subsequent NO production. 1400W, an iNOS inhibitor, suppressed the IL-1β-induced apoptosis. Levosimendan alone-treatment concentration-dependently increased phosphorylation of Akt (Ser473). LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, reversed the protective effect of levosimendan on IL-1β-induced apoptosis in TUNEL assay. In addition, levosimendan and 1400W inhibited the IL-1β-induced cytosolic translocation of cytochrome-c. LY294002 reversed the suppressive effects of levosimendan. The present study for the first time demonstrated that levosimendan inhibits IL-1β-induced apoptosis via the activation of PI3K/Akt pathway and the inhibition of iNOS expression in adult rat cardiac fibroblasts.

Authors+Show Affiliations

Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada city, Aomori 034-8628, Japan. Electronic address: mokada@vmas.kitasato-u.ac.jp.Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada city, Aomori 034-8628, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26528797

Citation

Okada, Muneyoshi, and Hideyuki Yamawaki. "Levosimendan Inhibits Interleukin-1β-induced Apoptosis Through Activation of Akt and Inhibition of Inducible Nitric Oxide Synthase in Rat Cardiac Fibroblasts." European Journal of Pharmacology, vol. 769, 2015, pp. 86-92.
Okada M, Yamawaki H. Levosimendan inhibits interleukin-1β-induced apoptosis through activation of Akt and inhibition of inducible nitric oxide synthase in rat cardiac fibroblasts. Eur J Pharmacol. 2015;769:86-92.
Okada, M., & Yamawaki, H. (2015). Levosimendan inhibits interleukin-1β-induced apoptosis through activation of Akt and inhibition of inducible nitric oxide synthase in rat cardiac fibroblasts. European Journal of Pharmacology, 769, 86-92. https://doi.org/10.1016/j.ejphar.2015.10.056
Okada M, Yamawaki H. Levosimendan Inhibits Interleukin-1β-induced Apoptosis Through Activation of Akt and Inhibition of Inducible Nitric Oxide Synthase in Rat Cardiac Fibroblasts. Eur J Pharmacol. 2015 Dec 15;769:86-92. PubMed PMID: 26528797.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Levosimendan inhibits interleukin-1β-induced apoptosis through activation of Akt and inhibition of inducible nitric oxide synthase in rat cardiac fibroblasts. AU - Okada,Muneyoshi, AU - Yamawaki,Hideyuki, Y1 - 2015/10/31/ PY - 2015/10/02/received PY - 2015/10/23/revised PY - 2015/10/30/accepted PY - 2015/11/4/entrez PY - 2015/11/4/pubmed PY - 2016/9/27/medline KW - Akt KW - Apoptosis KW - Cardiac fibroblasts KW - Inducible nitric oxide synthase KW - Levosimendan SP - 86 EP - 92 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 769 N2 - Levosimendan, a calcium sensitizer, known as an inotropic agent has a cytoprotective effect against apoptosis in cardiomyocytes. However, the cytoprotective effect of levosimendan on cardiac fibroblasts has not been clarified. The aim of this study was to examine whether levosimendan modulates interleukin (IL)-1β-induced apoptosis in adult rat cardiac fibroblast. Cardiac fibroblasts were isolated from adult male Wistar rats. Apoptosis of cardiac fibroblasts was evaluated by 4',6-diamidino-2-phenylindole staining and TdT-mediated d-UTP nick end labeling (TUNEL)-based staining. Expression of inducible nitric oxide (NO) synthase (iNOS) and phosphorylation of Akt (Ser473) were determined by Western blotting. Assessment of NO production in the culture medium was performed by using 4,5-diaminofluorescein as a fluorescent probe. Immunofluorescence staining was performed to examine cytochrome-c translocation. Levosimendan (3-100μM) concentration-dependently inhibited IL-1β (4ng/ml, 24h)-induced apoptotic changes in cardiac fibroblasts, such as cellular shrinkage, nuclear condensation and the increase of TUNEL-positive cells. Levosimendan inhibited IL-1β-induced iNOS expression and subsequent NO production. 1400W, an iNOS inhibitor, suppressed the IL-1β-induced apoptosis. Levosimendan alone-treatment concentration-dependently increased phosphorylation of Akt (Ser473). LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, reversed the protective effect of levosimendan on IL-1β-induced apoptosis in TUNEL assay. In addition, levosimendan and 1400W inhibited the IL-1β-induced cytosolic translocation of cytochrome-c. LY294002 reversed the suppressive effects of levosimendan. The present study for the first time demonstrated that levosimendan inhibits IL-1β-induced apoptosis via the activation of PI3K/Akt pathway and the inhibition of iNOS expression in adult rat cardiac fibroblasts. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/26528797/Levosimendan_inhibits_interleukin_1β_induced_apoptosis_through_activation_of_Akt_and_inhibition_of_inducible_nitric_oxide_synthase_in_rat_cardiac_fibroblasts_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(15)30337-X DB - PRIME DP - Unbound Medicine ER -