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Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction.
Cardiovasc Res. 2004 Dec 01; 64(3):526-35.CR

Abstract

OBJECTIVE

Transforming growth factor (TGF)-beta promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts.

METHODS

Anterior MI was produced in mice by ligating the left coronary artery. TGF-beta mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-beta signaling during the early phase of MI, an extracellular domain of TGF-beta type II receptor (TbetaIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation.

RESULTS

TbetaIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-beta signaling during the later phase, TbetaIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TbetaIIR.

CONCLUSIONS

The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.

Authors+Show Affiliations

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15537506

Citation

Ikeuchi, Masaki, et al. "Inhibition of TGF-beta Signaling Exacerbates Early Cardiac Dysfunction but Prevents Late Remodeling After Infarction." Cardiovascular Research, vol. 64, no. 3, 2004, pp. 526-35.
Ikeuchi M, Tsutsui H, Shiomi T, et al. Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res. 2004;64(3):526-35.
Ikeuchi, M., Tsutsui, H., Shiomi, T., Matsusaka, H., Matsushima, S., Wen, J., Kubota, T., & Takeshita, A. (2004). Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovascular Research, 64(3), 526-35.
Ikeuchi M, et al. Inhibition of TGF-beta Signaling Exacerbates Early Cardiac Dysfunction but Prevents Late Remodeling After Infarction. Cardiovasc Res. 2004 Dec 1;64(3):526-35. PubMed PMID: 15537506.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. AU - Ikeuchi,Masaki, AU - Tsutsui,Hiroyuki, AU - Shiomi,Tetsuya, AU - Matsusaka,Hidenori, AU - Matsushima,Shouji, AU - Wen,Jing, AU - Kubota,Toru, AU - Takeshita,Akira, PY - 2004/05/20/received PY - 2004/07/23/revised PY - 2004/07/24/accepted PY - 2004/11/13/pubmed PY - 2005/2/18/medline PY - 2004/11/13/entrez SP - 526 EP - 35 JF - Cardiovascular research JO - Cardiovasc Res VL - 64 IS - 3 N2 - OBJECTIVE: Transforming growth factor (TGF)-beta promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts. METHODS: Anterior MI was produced in mice by ligating the left coronary artery. TGF-beta mRNA levels increased in both infarcted and noninfarcted LV after MI. To block TGF-beta signaling during the early phase of MI, an extracellular domain of TGF-beta type II receptor (TbetaIIR) plasmid was transfected into the limb skeletal muscles 7 days before ligation. RESULTS: TbetaIIR increased the mortality during 24 h of MI, as well as exacerbated LV dilatation and contractile dysfunction, the infiltration of neutrophils, and gene expression of tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1 compared with nontreated MI mice despite the comparable infarct size. Next, to block TGF-beta signaling during the later phase, TbetaIIR was transfected into mice at days 0 and 7 after ligation. At 4 weeks, LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV seen in MI mice were prevented by TbetaIIR. CONCLUSIONS: The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/15537506/Inhibition_of_TGF_beta_signaling_exacerbates_early_cardiac_dysfunction_but_prevents_late_remodeling_after_infarction_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/j.cardiores.2004.07.017 DB - PRIME DP - Unbound Medicine ER -