Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction

Shunsuke Tamaki, Toshiaki Mano, Yasushi Sakata, Tomohito Ohtani, Yasuharu Takeda, Daisuke Kamimura, Yosuke Omori, Yasumasa Tsukamoto, Yukitoshi Ikeya, Mari Kawai, Atsushi Kumanogoh, Keisuke Hagihara, Ryohei Ishii, Mitsuru Higashimori, Makoto Kaneko, Hidetoshi Hasuwa, Takeshi Miwa, Kazuhiro Yamamoto, Issei Komuro

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background:Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process.Methods and Results:An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.Conclusion:Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Original languageEnglish
Article numbere68893
JournalPLoS One
Volume8
Issue number7
DOIs
Publication statusPublished - 2013 Jul 19
Externally publishedYes

Fingerprint

Interleukin-16
interleukins
heart failure
fibrosis
Fibrosis
Heart Failure
animal models
Stroke Volume
Rats
Assays
Serum
Immunosorbents
therapeutics
angiotensin II
Macrophages
Left Ventricular Dysfunction
Neutralizing Antibodies
neutralizing antibodies
Infiltration
Angiotensin II

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tamaki, S., Mano, T., Sakata, Y., Ohtani, T., Takeda, Y., Kamimura, D., ... Komuro, I. (2013). Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction. PLoS One, 8(7), [e68893]. https://doi.org/10.1371/journal.pone.0068893

Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction. / Tamaki, Shunsuke; Mano, Toshiaki; Sakata, Yasushi; Ohtani, Tomohito; Takeda, Yasuharu; Kamimura, Daisuke; Omori, Yosuke; Tsukamoto, Yasumasa; Ikeya, Yukitoshi; Kawai, Mari; Kumanogoh, Atsushi; Hagihara, Keisuke; Ishii, Ryohei; Higashimori, Mitsuru; Kaneko, Makoto; Hasuwa, Hidetoshi; Miwa, Takeshi; Yamamoto, Kazuhiro; Komuro, Issei.

In: PLoS One, Vol. 8, No. 7, e68893, 19.07.2013.

Research output: Contribution to journalArticle

Tamaki, S, Mano, T, Sakata, Y, Ohtani, T, Takeda, Y, Kamimura, D, Omori, Y, Tsukamoto, Y, Ikeya, Y, Kawai, M, Kumanogoh, A, Hagihara, K, Ishii, R, Higashimori, M, Kaneko, M, Hasuwa, H, Miwa, T, Yamamoto, K & Komuro, I 2013, 'Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction', PLoS One, vol. 8, no. 7, e68893. https://doi.org/10.1371/journal.pone.0068893
Tamaki, Shunsuke ; Mano, Toshiaki ; Sakata, Yasushi ; Ohtani, Tomohito ; Takeda, Yasuharu ; Kamimura, Daisuke ; Omori, Yosuke ; Tsukamoto, Yasumasa ; Ikeya, Yukitoshi ; Kawai, Mari ; Kumanogoh, Atsushi ; Hagihara, Keisuke ; Ishii, Ryohei ; Higashimori, Mitsuru ; Kaneko, Makoto ; Hasuwa, Hidetoshi ; Miwa, Takeshi ; Yamamoto, Kazuhiro ; Komuro, Issei. / Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction. In: PLoS One. 2013 ; Vol. 8, No. 7.
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AU - Ishii, Ryohei

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AU - Kaneko, Makoto

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