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Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.

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 - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

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.

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Effect of enhanced cardiac expression of interleukin-16 (IL-16) on markers of cardiac fibrosis in mice.A through C, Left ventricular mRNA levels of Collagen I (A), transforming growth factor-beta 1 (TGF-β1) (B) and connective tissue growth factor (CTGF) (C) in non-transgenic (Non-TG) and transgenic (TG) mice. D through F, Left ventricular protein levels of Collagen I (D), TGF-β1 (E) and CTGF (F) in Non-TG and TG mice. Top panels in each figure show a representative Western blot. n = 5 per group. G and H, Correlations of IL-16 mRNA levels with AOF (G) and Young’s modulus EH (H) in TG mice.
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pone-0068893-g004: Effect of enhanced cardiac expression of interleukin-16 (IL-16) on markers of cardiac fibrosis in mice.A through C, Left ventricular mRNA levels of Collagen I (A), transforming growth factor-beta 1 (TGF-β1) (B) and connective tissue growth factor (CTGF) (C) in non-transgenic (Non-TG) and transgenic (TG) mice. D through F, Left ventricular protein levels of Collagen I (D), TGF-β1 (E) and CTGF (F) in Non-TG and TG mice. Top panels in each figure show a representative Western blot. n = 5 per group. G and H, Correlations of IL-16 mRNA levels with AOF (G) and Young’s modulus EH (H) in TG mice.

Mentions: The enhanced expression of the bioactive secreted form of IL-16 in the heart of TG mice was confirmed by Western blotting (Figure 3A), whereas there was no significant difference in serum IL-16 levels between TG (32.1±6.8 pg/ml) and Non-TG (31.3±6.0 pg/ml) mice. Atrial enlargement was observed (Table 5 and Figure 3B) and the extent of LV fibrosis was increased (Figure 3C) in the TG mice. Moreover, an index of LV myocardial stiffness, Young’s modulus EH, was also increased in the TG mice (Figure 3D). LV mRNA and protein levels of Collagen I, TGF-β1 and CTGF were also increased in the TG mice (Figure 4A through F). The LV IL-16 mRNA level was positively correlated with both the extent of LV fibrosis and EH in the TG mice (Figure 4G and H).


Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.

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 - PLoS ONE (2013)

Effect of enhanced cardiac expression of interleukin-16 (IL-16) on markers of cardiac fibrosis in mice.A through C, Left ventricular mRNA levels of Collagen I (A), transforming growth factor-beta 1 (TGF-β1) (B) and connective tissue growth factor (CTGF) (C) in non-transgenic (Non-TG) and transgenic (TG) mice. D through F, Left ventricular protein levels of Collagen I (D), TGF-β1 (E) and CTGF (F) in Non-TG and TG mice. Top panels in each figure show a representative Western blot. n = 5 per group. G and H, Correlations of IL-16 mRNA levels with AOF (G) and Young’s modulus EH (H) in TG mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3716890&req=5

pone-0068893-g004: Effect of enhanced cardiac expression of interleukin-16 (IL-16) on markers of cardiac fibrosis in mice.A through C, Left ventricular mRNA levels of Collagen I (A), transforming growth factor-beta 1 (TGF-β1) (B) and connective tissue growth factor (CTGF) (C) in non-transgenic (Non-TG) and transgenic (TG) mice. D through F, Left ventricular protein levels of Collagen I (D), TGF-β1 (E) and CTGF (F) in Non-TG and TG mice. Top panels in each figure show a representative Western blot. n = 5 per group. G and H, Correlations of IL-16 mRNA levels with AOF (G) and Young’s modulus EH (H) in TG mice.
Mentions: The enhanced expression of the bioactive secreted form of IL-16 in the heart of TG mice was confirmed by Western blotting (Figure 3A), whereas there was no significant difference in serum IL-16 levels between TG (32.1±6.8 pg/ml) and Non-TG (31.3±6.0 pg/ml) mice. Atrial enlargement was observed (Table 5 and Figure 3B) and the extent of LV fibrosis was increased (Figure 3C) in the TG mice. Moreover, an index of LV myocardial stiffness, Young’s modulus EH, was also increased in the TG mice (Figure 3D). LV mRNA and protein levels of Collagen I, TGF-β1 and CTGF were also increased in the TG mice (Figure 4A through F). The LV IL-16 mRNA level was positively correlated with both the extent of LV fibrosis and EH in the TG mice (Figure 4G and H).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

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.

Show MeSH
Related in: MedlinePlus