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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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Related in: MedlinePlus

Enhanced cardiac expression of interleukin-16 induces cardiac macrophage infiltration in mice.A, Representative photomicrographs of immunofluorescence staining of the left ventricle for F4/80 in non-transgenic (Non-TG) and transgenic (TG) mice. Bar = 50 µm. B, Left ventricular mRNA levels of F4/80 in Non-TG and TG mice. C, Quantitative analysis of macrophage infiltration into left ventricular myocardium in Non-TG and TG mice. n = 6 per group.
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pone-0068893-g005: Enhanced cardiac expression of interleukin-16 induces cardiac macrophage infiltration in mice.A, Representative photomicrographs of immunofluorescence staining of the left ventricle for F4/80 in non-transgenic (Non-TG) and transgenic (TG) mice. Bar = 50 µm. B, Left ventricular mRNA levels of F4/80 in Non-TG and TG mice. C, Quantitative analysis of macrophage infiltration into left ventricular myocardium in Non-TG and TG mice. n = 6 per group.

Mentions: Inflammatory cells, especially infiltrating monocytes and macrophages in the heart, have been suggested to have a crucial role in cardiac fibrosis [17], [37], [38], whereas IL-16 has been reported to be able to chemoattract monocytes [39]. Therefore, we examined macrophage infiltration into LV myocardium of TG mice and assessed the direct effect of IL-16 on cultured macrophages. Macrophages were significantly increased in the left ventricle of TG mice (Figure 5A through C). In addition, when stimulated with recombinant murine IL-16, mouse peritoneal macrophages released TGF-β1 in a dose-dependent manner (Figure 6A). Confocal immunofluorescence microscopy revealed that many F4/80-positive macrophages colocalized with TGF-β1 in the left ventricle of TG mice compared with Non-TG mice (Figure 6B). These data suggested that IL-16 might be at least one of the cytokines playing a central role in the promotion of cardiac fibrosis through the release of TGF-β1 from the infiltrating and resident macrophages in TG mice.


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)

Enhanced cardiac expression of interleukin-16 induces cardiac macrophage infiltration in mice.A, Representative photomicrographs of immunofluorescence staining of the left ventricle for F4/80 in non-transgenic (Non-TG) and transgenic (TG) mice. Bar = 50 µm. B, Left ventricular mRNA levels of F4/80 in Non-TG and TG mice. C, Quantitative analysis of macrophage infiltration into left ventricular myocardium in Non-TG and TG mice. n = 6 per group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0068893-g005: Enhanced cardiac expression of interleukin-16 induces cardiac macrophage infiltration in mice.A, Representative photomicrographs of immunofluorescence staining of the left ventricle for F4/80 in non-transgenic (Non-TG) and transgenic (TG) mice. Bar = 50 µm. B, Left ventricular mRNA levels of F4/80 in Non-TG and TG mice. C, Quantitative analysis of macrophage infiltration into left ventricular myocardium in Non-TG and TG mice. n = 6 per group.
Mentions: Inflammatory cells, especially infiltrating monocytes and macrophages in the heart, have been suggested to have a crucial role in cardiac fibrosis [17], [37], [38], whereas IL-16 has been reported to be able to chemoattract monocytes [39]. Therefore, we examined macrophage infiltration into LV myocardium of TG mice and assessed the direct effect of IL-16 on cultured macrophages. Macrophages were significantly increased in the left ventricle of TG mice (Figure 5A through C). In addition, when stimulated with recombinant murine IL-16, mouse peritoneal macrophages released TGF-β1 in a dose-dependent manner (Figure 6A). Confocal immunofluorescence microscopy revealed that many F4/80-positive macrophages colocalized with TGF-β1 in the left ventricle of TG mice compared with Non-TG mice (Figure 6B). These data suggested that IL-16 might be at least one of the cytokines playing a central role in the promotion of cardiac fibrosis through the release of TGF-β1 from the infiltrating and resident macrophages in TG mice.

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