Elsevier

Journal of Cardiac Failure

Volume 7, Issue 4, December 2001, Pages 355-364
Journal of Cardiac Failure

Experimental Studies
Myocardial hypertrophy in transgenic mice overexpressing human interleukin 1α*

https://doi.org/10.1054/jcaf.2001.28221Get rights and content

Abstract

Background: Interleukin (IL)-1 has profound effects on nonimmune cells and organs, including the heart. The effects of IL-1 on transgenic hearts have not yet been described. Methods and Results: We generated transgenic mice overexpressing the human IL-1 gene under control of the cytomegalovirus enhancer/chicken β-actin promoter. Heart weight–body weight ratio increased 1.4- to 2.2-fold in transgenic mice compared with wild-type mice. Lung weight–body weight ratio also increased in transgenic mice, all of which died within 14 days of birth. Light microscopy revealed concentric hypertrophy with cardiomyocyte hypertrophy in all transgenic mice and pulmonary edema in some of them. Electron microscopy showed myofilament loss and an increased number of giant mitochondria, but no sarcomere disarray. Northern blotting showed that gene expression had been reprogrammed in the left ventricle of transgenic mice. Expression of fetal-type genes such as prepro–atrial natriuretic factor and β-myosin heavy chain were increased, but voltage-dependent calcium channel messenger RNA expression was decreased in the left ventricle of transgenic mice compared with that of wild-type mice. Conclusions: IL-1 may cause structural and functional alterations in cardiac myocytes.

Section snippets

Construction of IL-1α transgene and generation of TG mice

Construction of the CAG–IL-1α transgene is shown in Fig. 1.

. Structures of CAG–IL-1α transgene. Shaded box indicates CAG promoter; open box indicates human IL-1α sequence; thick line indicates rabbit β-globin gene; ATG indicates translation initiation site. Apa, ApaI; B, BamHI; CAG, gene encoding cytomegalovirus enhancer, chicken β-actin promoter, and first intron of chicken β-actin gene; Dra, DraI; E, EcoRI; K, KpnI; N, NotI; P, PstI; pA, polyA signal site of rabbit β-globin gene; S, SacI; Sm,

TG mice

Changes were more severe in all tested tissues from 1 of the 2 lines. We report characterization of the founder and F1 offspring from this line. Table 1 shows hIL-1α levels determined by ELISA in 12-day-old TG and WT mice.

. Tissue hIL-1α protein levels

Empty CellhIL-1α (pg/mL)
Empty CellTG (n = 6)WT (n = 12)
Ventricle113 ± 32*<4
Atrium78 ± 19*<4
Lung50 ± 8*<4
Liver135 ± 31*<4
Serum69 ± 12*<4
*P <.01 v WT.

Values are means ± SD.

hIL-1α levels were significantly higher in TG than WT mice (P <.01). In TG mice growth was stunted

Discussion

In this study we show that constitutively increased levels of hIL-1α in the hearts of TG mice produce cardiomyocyte hypertrophy and heart failure. The developmental overexpression of hIL-1α produced excessive cardiac growth in all TG F1 mice, all of which died before weaning. Northern blotting detected hIL-1α gene expression, and ELISA revealed substantial amounts of hIL-1α protein in TG hearts. Therefore, although we examined only TG F1 mice, we conclude that this cardiac growth response was a

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    *

    Reprint requests: Kikuo Isoda, MD, First Department of Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-0042 Japan.

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