Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy - PubMed (original) (raw)
Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy
K Kunisada et al. Proc Natl Acad Sci U S A. 2000.
Abstract
The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase families and plays a pivotal role in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (STAT3-TG) were generated. STAT3-TG manifested myocardial hypertrophy at 12 wk of age with increased expression of the atrial natriuretic factor (ANF), beta-myosin heavy chain (MHC), and cardiotrophin (CT)-1 genes. The animals were injected i.p. with 15 mg/kg doxorubicin (Dox), an antineoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (5/20) for control littermates (WT), but 80% (16/20) for STAT3-TG (P < 0.01). WT showed increased expression of beta-MHC and ANF mRNAs in the hearts 1 day after Dox treatment; this expression peaked at 3 days, suggesting that the WT suffered from congestive heart failure. Although the expression of these mRNAs was elevated in STAT3-TG hearts before Dox treatment, no additional increase was observed after the treatment. Dox administration significantly reduced the expression of the cardiac alpha-actin and Stat3 genes in WT hearts but not in STAT3-TG. These results provide direct evidence that STAT3 transduces not only a hypertrophic signal but also a protective signal against Dox-induced cardiomyopathy by inhibiting reduction of cardiac contractile genes and inducing cardiac protective factors.
Figures
Figure 1
Transgene construct and STAT3 expression in the hearts. (A) Schematic representation of the transgene, a 2.3-kb murine Stat3 cDNA was ligated downstream of a 5.5-kb fragment of the murine α-myosin heavy chain (MHC) gene promoter and upstream of a 0.6-kb human growth hormone (hGH) poly(A). (B) Northern blot analysis was performed using a murine Stat3 cDNA as a probe. Hearts from transgene-positive animals (TG12 and TG22) showed abundant Stat3 mRNA expression. Equal RNA loadings were documented by 28S RNA (Lower). (C) gp130, JAK1, and STAT3 expressions in the hearts. The lysates from the hearts containing equal amounts of the protein (10 μg) were separated by SDS/PAGE and immunoblotted with rabbit anti-gp130, JAK1, or STAT3 Ab as described in Materials and Methods. WT, Control littermate; TG, STAT3-TG.
Figure 2
Histological analysis of the hearts. The sections obtained from the hearts of 3-mo-old control mice and STAT3-TG were stained with hematoxylin/eosin. (Magnification: ×20.)
Figure 3
Induction of the hypertrophy genes program in STAT3 transgenic mice. (A) Semiquantitative RT-PCR analysis. Equal volumes of the amplified PCR products were loaded onto a 1.5% agarose gel. (B) Northern blot analysis using a CT-1 cDNA as a probe. WT, Control littermate; TG, STAT3-TG.
Figure 4
Survival rates for the mice treated with Dox. Three-month-old STAT3-TG and WT mice weighing 21–23 g (n = 20) were injected i.p. with Dox at a single dose of 15 mg/kg and bred under normal condition. Kaplan–Meier survival curves represent significantly better survival (P < 0.01) in STAT3-TG than in WT.
Figure 5
Alteration of cardiac gene expressions after Dox treatment. WT and STAT3-TG were treated with single dose of 15 mg/kg Dox, and the hearts were excised after 2 days. Northern blot analysis was performed using a cardiac α-actin cDNA (A) or a murine Stat3 cDNA (B) as a probe. Equal RNA loadings were documented by 28S RNA and β-actin controls. WT, Control littermate; TG, STAT3-TG.
Figure 6
Expression of β-MHC and ANF mRNAs after Dox treatment. Semiquantitative RT-PCR was performed as described in Fig. 3. RNAs were obtained from the hearts at the indicated day after 15 mg/kg Dox treatment. WT, Control littermate; TG, STAT3-TG.
Similar articles
- Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes.
Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T. Kunisada K, et al. Circulation. 1998 Jul 28;98(4):346-52. doi: 10.1161/01.cir.98.4.346. Circulation. 1998. PMID: 9711940 - gp130-Dependent signalling pathway is not enhanced in gp130 transgenic heart after LIF stimulation.
Tone E, Kunisada K, Kumanogoh A, Negoro S, Funamoto M, Osugi T, Kishimoto T, Yamauchi-Takihara K. Tone E, et al. Cytokine. 2000 Oct;12(10):1512-8. doi: 10.1006/cyto.2000.0751. Cytokine. 2000. PMID: 11023666 - Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein.
Wang L, Zhang TP, Zhang Y, Bi HL, Guan XM, Wang HX, Wang X, Du J, Xia YL, Li HH. Wang L, et al. Sci Rep. 2016 Jun 21;6:28399. doi: 10.1038/srep28399. Sci Rep. 2016. PMID: 27323684 Free PMC article. - A novel role for STAT3 in cardiac remodeling.
Yamauchi-Takihara K, Kishimoto T. Yamauchi-Takihara K, et al. Trends Cardiovasc Med. 2000 Oct;10(7):298-303. doi: 10.1016/s1050-1738(01)00066-4. Trends Cardiovasc Med. 2000. PMID: 11343970 Review. - Induction of S100b in myocardium: an intrinsic inhibitor of cardiac hypertrophy.
Parker TG, Marks A, Tsoporis JN. Parker TG, et al. Can J Appl Physiol. 1998 Aug;23(4):377-89. doi: 10.1139/h98-022. Can J Appl Physiol. 1998. PMID: 9677434 Review.
Cited by
- The functional role of m6A demethylase ALKBH5 in cardiomyocyte hypertrophy.
Meng C, Su H, Shu M, Shen F, Lu Y, Wu S, Su Z, Yu M, Yang D. Meng C, et al. Cell Death Dis. 2024 Sep 18;15(9):683. doi: 10.1038/s41419-024-07053-2. Cell Death Dis. 2024. PMID: 39294131 Free PMC article. - Exploring the mechanism of curcumin in the treatment of doxorubicin-induced cardiotoxicity based on network pharmacology and molecular docking technology.
Hu Z. Hu Z. Medicine (Baltimore). 2024 Feb 16;103(7):e36593. doi: 10.1097/MD.0000000000036593. Medicine (Baltimore). 2024. PMID: 38363942 Free PMC article. - Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin.
Karmazyn M, Gan XT. Karmazyn M, et al. Int J Mol Sci. 2024 Jan 17;25(2):1137. doi: 10.3390/ijms25021137. Int J Mol Sci. 2024. PMID: 38256208 Free PMC article. Review. - CD9 exacerbates pathological cardiac hypertrophy through regulating GP130/STAT3 signaling pathway.
Li Y, Fan S, Kong L, Hao Z, Zhou Y, Shangguan J, Gao L, Wang M, Kang Y, Li X, Huang K, Zhang C, Liu Z. Li Y, et al. iScience. 2023 Sep 28;26(11):108070. doi: 10.1016/j.isci.2023.108070. eCollection 2023 Nov 17. iScience. 2023. PMID: 37860696 Free PMC article. - Leucine zipper protein 1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling.
Fan D, Jiang WL, Jin ZL, Cao JL, Li Y, He T, Zhang W, Peng L, Liu HX, Wu XY, Chen M, Fan YZ, He B, Yu WX, Wang HR, Hu XR, Lu ZB. Fan D, et al. J Adv Res. 2024 Sep;63:117-128. doi: 10.1016/j.jare.2023.10.007. Epub 2023 Oct 6. J Adv Res. 2024. PMID: 37806546 Free PMC article.
References
- Kishimoto T, Taga T, Akira S. Cell. 1994;76:253–262. - PubMed
- Akira S, Nishio Y, Inoue M, Wang X J, Wei S, Yoshida K, Sudo T, Naruo M, Kishimoto T. Cell. 1994;77:63–71. - PubMed
- Ruff-Jamison S, Zhong Z, Wen Z, Chen K, Darnell J E, Jr, Cohen S. J Biol Chem. 1994;269:21933–21935. - PubMed
- Campbell G S, Meyer D J, Raz R, Levy D E, Schwartz J, Carter-Su C. J Biol Chem. 1995;270:3974–3979. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous