High-Fructose Diet Induces Cardiac Dysfunction via Macrophage Recruitment in Adult Mice

Abstract

Cardiovascular diseases are the leading cause of death globally, including cardiac fibrosis, myocardial infarction, cardiac hypertrophy, and heart failure. High fat/ fructose induces metabolic syndrome, hypertension and obesity, which contributes to cardiac hypertrophy and fibrosis. Excessive fructose intake accelerates inflammation in different organs and tissues, and molecular and cellular mechanisms of organ and tissue injury have been demonstrated. However, the mechanisms of cardiac inflammation have not been fully documented in high-fructose diet. This study shows that there are significantly increased in cardiomyocytes size and relative wall thickness of LV in high-fructose fed adult mice. With echocardiographic analysis of cardiac function, the ejection fraction (EF%) and fractional shortening (FS%) are significantly reduced at 12 weeks after 60% high-fructose diet. The mRNA and protein levels of MCP-1 are notably increased in high-fructose treated HL-1 and primary cardiomyocyte respectively. Also, the increased protein level of MCP-1 has been detected in vivo mouse model after 12 weeks feeding, resulting in the production of pro-inflammatory makers, pro-fibrotic genes expression, and macrophage infiltration. These data demonstrate that high-fructose intake induces cardiac inflammation via macrophage recruitment in cardiomyocyte, which contributes to impair cardiac function.

Keywords

cardiac disease cardiac hypertrophy cardiac fibrosis macrophage infiltration inflammatory response

Introduction

Cardiac dysfunction is the most common cause of death around the world. Hypertension, obesity, myocardial infarction and other metabolic diseases contribute to pathological cardiac hypertrophy.¹ High fat/fructose intake induces metabolic syndrome, hypertension, insulin resistance, vascular dysfunction and inflammation, leading to cardiac hypertrophy and fibrosis. Also, excessive fructose consumption accelerates inflammation in heart, brain, liver, kidney and gut by regulating inflammatory response.^2,3 Mounting studies suggested that fructose induced oxidative stress,⁴ NLRP3 signaling,⁵ mitogen-activated protein kinases (MAPK) signaling,⁶ mitochondrial signaling pathway,⁷ and inflammatory signaling.⁸ Understanding how cardiac inflammation provides potentially valuable information for administrating cardiac dysfunction.

Dietary habits affect human health, and the consumption of fructose gradually increases in daily diets. Excessive fructose intake elevates diastolic blood pressure, resulting in arterial hypertension.⁹ Cardiac hypertrophy is one of severe complications of persistent high blood pressure and leads to eccentric heart dilation and cardiac dysfunction, including dilated cardiomyocytes, cardiomyocytes apoptosis, and induced upregulation of pro-fibrotic genes.^10,11 Accumulating evidences showed that excessive fructose consumption induces cardiac hypertrophy with several different mechanisms.^1
-3,7 There is not only hypertension induces cardiac hypertrophy, but also inflammatory response. In context of inflammation, 10-weeks high fructose feeding stimulates NLRP3 inflammasome activation by inducing CD36 expression and cardiac oxidative stress.⁵ Fructose exposure upregulates the expression of p38, ERK1/2, and JNK and then activates MAPKs pathways as well.⁶ In addition, excessive intake of fructose increases the expression of TNF-α, IL-6, IL-1β, and NF-κB in rat cardiac tissues, leading to cardiac inflammation in fructose-fed diabetic rats.¹² More importantly, high-fructose exposure regulates immune cell activation in dendritic cells, demonstrating that the production of IL-6, IL-1β, and interferon-γ significantly increased in fructose stimulation in vitro. ¹³ Mounting findings suggested that fructose promotes inflammation of LPS-stimulated mononuclear phagocytes and macrophages as well as increases serum cytokine levels of IL-1β, IL-6 and TNF-α, but there is no difference in promoting in inflammatory subsets of T cells.^8,14

MCP-1 (Monocyte chemoattractant protein-1), which is a key mediator in proinflammatory response, promoted inflammation and immune cells infiltration in human diseases. Accumulating evidences demonstrate that excessive fructose induces MCP-1 expression during the process of organ injury and metabolic diseases. For instance, high fructose increases MCP-1 expression in mice model, which exacerbates liver injury in high-fat induced fatty liver.¹⁵ Also, fructose stimulation results in MCP-1 production of tubular cells and then promotes the chronic kidney injury in rat model.¹⁶ In context of cardiovascular diseases, MCP-1 is responsible for the monocytes migration in injured site and induced atherosclerosis,¹⁷ ischemic heart disease,^18,19 endothelial dysfunction,^20,21 and cardiac fibrosis.²² However, whether high-fructose induced MCP-1 expression has not been investigated in heart diseases.

Here, we establish high fructose induced cardiac dysfunction in adult C57BJ/L6 mice model, and then perform cellular and molecular experiments as well as echocardiographic analysis. High-fructose consumption not only induces cardiac dysfunction, but also increases MCP-1 expression in high-fructose treated HL-1 and primary cardiomyocyte, respectively. Furthermore, the mRNA and protein levels of MCP-1 are upregulated in hypertrophic cardiomyocyte after 12-weeks high-fructose feeding, which significantly stimulates the production of pro-inflammatory markers (IL-6, TNF-α, and COX-2) and cell adhesion molecules (ICAM-I and VCAM-I). On the other hand, excessive fructose consumption promotes F4/80+ macrophages infiltration and aggravates cardiac fibrosis in adult heart, suggesting high-fructose diet contributes to cardiac dysfunction and inflammation by regulating inflammatory response.

Materials and Methods

Animal Procedures

The care of laboratory animal and the animal experimental operations were approved by the Ethics Review Committee of Guangdong Medical University(ID number: GDY2002022)according to Administration Rule of Laboratory Animal. All animal were treated and analyzed in a blinded manner.

Animal and Fructose Treatment

Adult male C57BL/6 J mice (Age: 6w-8w) were procured from Guangdong Yaokang Biotechnology Co., Ltd. (Foshan, Guangdong, China). 35% and 60% Fructose feed were procured from TROPHIC Animal Feed High-Tech Co. Ltd (Nantong, Guangxi, China). Mice were sacrificed at 12 weeks for 35% and 60% fructose treated or non-treated mice.

Primary Cardiac Myocytes Isolation

The isolation of primary cardiac myocytes was performed as described in previous study.²³ Briefly, adult Institute of Cancer Research (ICR) mice aged 6-10 weeks were anesthetized and maintained with 2% isofluorane in 95% oxygen for 2–3 min. The skin of chest was cut, the ribs were excised, and then the heart and lungs were exposed. After washing heart with EDTA buffer, the descending aorta was clamped, and consequently digested the left ventricle (LV) of one mouse was injected with EDTA buffer (10 mL, 6 min), perfusion buffer (5 mL, 2 min), and collagenase buffer (10 mL, 5 min). The right ventricle was removed and the LV was gently excised and all of small pieces were resuspend with 1 mL pipette tips. Finally, adding 5 mL stop buffer inhibited enzyme activity. Harvested cardiac myocytes was washing with DMEM once time and then were cultured with C199 medium at 37°C with 5% CO₂.

Cells and Cell Culture

HL-1 cells were purchased from Hunan Fenghui Biotechnology Co., Ltd. (Changsha, Hunan, China) The HL-1 cells were cultured in DMEM medium with penicillin/streptomycin and 10% fetal bovine serum (Gibco, USA). All cell lines were cultured in 5% CO₂ at 37°.

Immunohistochemistry and Masson Staining

Mouse hearts were perfused and fixed in 4% paraformaldehyde at 4°C overnight. The fixed heart was dehydrated in a Dehydrator (Donatello, DIAPATH, Italy) and embedded in an Embedding machine (JB-P5, Wuhan Junjie Electronics Co., Ltd, Wuhan, China) and then stained with H&E staining kit (Servicebio, Wuhan, China), immunohistochemistry (Servicebio, Wuhan, China), and Masson staining (Servicebio, Wuhan, China) in accordance with the manufacturer’s instructions. Quantification of fibrosis density was calculated the blue-stained areas between cardiomyocytes relative to total area in each photograph using ImageJ (National Institutes of Health). The primary antibody of macrophage staining: F4/80(CST, Cat#30325)

Measurement of Cell Surface Area

All stained images were analyzed under a microscope (Mshot, MF43-N, Gangzhou, China or Nikon Eclipse E100, Japan). The area of cardiomyocytes was calculated with a statistical analysis as previously described.²⁴ The cardiomyocytes size was calculated with ImageJ software (National Institute of Health, Bethesda, MD, USA). The formula of relative wall thickness (%): 100% × the mean value of wall thickness × 2 of LV /the mean value of the maximum of LV length plus the minimum of LV length.

Quantitative Real-Time PCR (qRT-PCR)

After collecting the specimens, total RNA of HL-1, primary CM, and adult heart tissue were extracted with TRIzol® reagent (Invitrogen, USA) according to the protocol. For cDNA synthesis, total RNA was reverse transcribed to Transcript First-Strand cDNA Synthesis SuperMix (Takara Bio Inc, Dalian, China) according to the instructions. The gene expression was normalized to GAPDH. Real-time PCR was performed with ABI 7500 Real-Time PCR System, and the results were calculated using the 2^-ΔΔCt method. The qRT-PCR primers sequence (5′-3′) of genes are listed in supplemental Table 1.

Enzyme-Linked Immunosorbent Assay (ELISA)

The cells and heart tissues were homogenized for 5-10 seconds and lysed for 30 min in ice-cold RIPA lysis buffer containing protease inhibitor cocktail (Roche, Indianapolis, IN, USA). After that, taking supernates and store samples at −80°. The protein level of MCP-1 was measured by MCP-1 ELISA kit (RK00381, ABclonal, Woburn, MA 01801), according to the manufacturer’s instructions.

Echocardiography

Mice were anesthetized and maintained with 1%-2% isofluorane in 95% oxygen. The heart rate of mouse was about 400-450 times/minute. Echocardigraphic M-mode images were obtained from a parasternal long-axis view and using ultrasound imaging system Vinno 6 software (VINNO6 LAB Imaging System, China). The LV systolic function was measured using a digital ultrasound imaging system Vinno 6 at 12 weeks following high fructose treatment or no treatment in adult mice. Conventional measurements of the LV were as follows: end-diastolic volume (EDVs), end-systolic volume (ESVs), ejection fraction (EF%), and fractional shortening (FS%). All mentioned indexes were calculated for each mouse in a blinded manner. Data are representative of biological replicates (n = 5 per group, mean ± SEM, *P < .05, **P < .01, ***P < .001).

Statistical Analysis

The results were presented as mean values ± standard error of mean (mean ± S.E.M), and data were performed using GraphPad Prism 8.0 software (NIH, USA). The 2 tailed Student’s t test was used to calculate statistical differences between 2 groups, while One-way ANOVA followed by Dunnett’s method for multiple comparisons were performed in more than 2 groups. *P < .05, **P < .01, and ***P < .001 are statistically significant.

Results

High Fructose Diet Contributes to Cardiac Dysfunction in Adult C57BJ/L6 Mice

High-fructose diet increased arterial blood pressure, leading to cardiac hypertrophy and vascular damage. Mounting studies have demonstrated that high-fructose consumption mediated nitric oxide (NO) production, endothelial nitric oxide synthase NOS (eNOS), and nicotinamide adenine dinucleotide phosphate oxidase (NOX), resulting in vascular dysfunction.^25

-28 On the other hand, increased arterial blood pressure promoted myocardial dysfunction and induced cardiac hypertrophy.¹⁰ Therefore, to identify the effect of high fructose diet on cardiac function, we studied cardiac function with echocardiography in adult C57BJ/L6 mice at 12 weeks after 35% and 60% fructose feeding (Figure 1A and B). Echocardiography of 35% and 60% fructose diet adult mice demonstrated that the volume of EDV and ESV increased significantly in 60% fructose fed mice compared to control mice or 35% fructose fed mice, respectively (Figure 1C). More importantly, there was a significant reduction of ejection fraction (EF%), and fractional shortening (FS%) in 60% high-fructose diet, but no difference in 35% fructose diet mice compared with control group (Figure 1D). Given that the echocardiographic analysis of cardiac function, our data showed that 60% high-fructose diet could cause cardiac dysfunction at 12 weeks in adult mice.

High Fructose Induces Hypertrophic Changes and Cardiac Fibrosis in Adult Mice

High-fructose induced cardiac hypertrophy has been well documented in cardiovascular diseases. Excessive fructose consumption increased the ratio of heart weight/body weight (HW/BW) (mg/g), cardiomyocyte size (mm²), fibrosis levels, and hypertrophic gene expression in mice after 15-weeks feeding.²⁹ To test whether 35% and 60% fructose diet induce cardiac hypertrophy at 12 weeks, Body weight (g), HW/BW (mg/g), cardiomyocyte size (mm²) and relative wall thickness (%) were measured at 12 weeks high-fructose feeding in adult mice (Figure 2A-D). There was no significant difference in body weight of 35%, and 60% fructose diet compared with control mice (Figure 2A). Also, the ratio of HW/BW was no significant change in 35%, and 60% fructose diet compared with control mice, respectively (Figure 2B). Surprisedly, cardiomyocyte size (mm²) and relative wall thickness (%) were significantly increased in both high-fructose diet mice compared to control mice, and the 60% fructose diet remarkably increased in cardiomyocyte size compared to 35% fructose diet after 12 weeks feeding (Figure 2C and D). Therefore, excessive fructose intake may contribute to cardiac hypertrophy, resulting in hypertrophic changes in adult mice.

To identify whether high-fructose diet results in cardiac fibrosis in adult mice, we performed Masson staining and qRT-PCR to check cardiac fibrosis and pro-fibrotic gene expression in high-fructose fed mice at 12 weeks. 60% high-fructose intake obviously promoted the progress of cardiac fibrosis, although there was no significant statistical difference (Figure 3A and B). Also, the mRNA levels of pro-fibrotic genes (TGF-β1, TGF-β2, and TGF-β3) were significantly upregulated in 60% high-fructose treated mice compared with that of control mice or 35% fructose treated mice (Figure 3C). Thus, our results indicated that high fructose consumption may contribute to promote cardiac fibrosis.

High Fructose Exposure Upregulates MCP-1 Expression in HL-1 and Primary Cardiomyocytes in Vitro

Accumulating evidences showed that high-fructose diet promoted inflammatory cytokines in mice, such as IL-6, TNF-α, IL-1β, IL-18, and MIP-2.^14,29,30 High-fructose intake mediated ROS-regulated PI3K/AKT signaling pathway,³¹ NLRP3 signaling activation by inducing cardiac oxidative stress,⁵ and MAPKs pathways,⁶ which was associated with inflammatory response in mice. Furthermore, animals fed fructose induced MCP-1 expression in chronic kidney injury compared with normal diet,¹⁶ and subsequently contributed to macrophages infiltration and aggravated cardiac injury.²² However, MCP-1 recruited macrophages contributed to clear necrotic debris and promoted wound healing in neonatal mice.³² Thus, we further investigated whether high-fructose induced MCP-1 expression in vitro, HL-1 cell lines and primary cardiomyocytes (CM) of ICR mice were exposure to different fructose final concentrations for 72 hours (0, 10 mM, 20 mM, 40 mM, and 80 mM). The mRNA level of MCP-1 of HL-1 and primary CM significantly increased in 40 mM and 80 mM fructose stimulation compared with untreated group, respectively (Figure 4A). Also, the protein level of MCP-1 was significantly upregulated in different fructose concentration stimulated HL-1 cell lines and primary CM (Figure 4B). Thus, our findings demonstrated that high fructose stimulation may induce MCP-1 expression, resulting in promoting inflammatory response in adult heart.

High Fructose Diet Induces MCP-1 Expression and Promotes Macrophage Infiltration in Adult Mice

To validate high-fructose diet induced inflammation via MCP-1 expression, we performed in vivo animal model to identify whether MCP-1 expression was induced in high fructose fed adult mice. Firstly, we performed qRT-PCR to detect MCP-1 expression in adult mice, demonstrating that 60% high-fructose consumption significantly induced MCP-1 expression in cardiac tissues compared with control group. Moreover, the mRNA level of MCP-1 upregulated in fructose-dose dependent manner (Figure 5A). On the other hand, our ELISA results illustrated that MCP-1 protein level of heart tissue was slightly reduced in 35% fructose fed adult mice at 12 weeks compared with control mice (−88.60 ± 46.65 pg/mL, mean ± SEM), but significantly increased in 60% fructose fed mice (140.0 ± 48.60 pg/mL, mean ± SEM) (Figure 5A).

MCP-1 is a key mediator of inflammation and immune response, which promotes inflammatory response and immune cells infiltration in human diseases. To check the role of upregulated MCP-1 on the production of inflammatory markers in adult heart after high-fructose feeding, we performed qRT-PCR to detect inflammatory stimuli. Our results showed that the mRNA levels of IL-6, TNF-α, and COX-2 significantly increased at 12 weeks after 60% fructose feeding compared with that of control mice, and meanwhile the mRNA levels of cell adhesion molecules ICAM-1, and VCAM-1, were induced in 60% fructose treated mice (Figure 5B). In context of inflammatory cells, we found that 60% high-fructose intake could promote F4/80+ macrophage infiltration surrounding the cardiac aorta compared to control or 35% fructose fed group, respectively (Figure 6A and B). These findings demonstrated that high fructose diet was directly associated with MCP-1 expression and then promoted macrophage infiltration in adult heart.

Discussion

Fructose-rich diets were associated with obesity, insulin resistance and diabetes, non-alcoholic fatty liver disease as well as cardiovascular diseases.^25,33 Fructose intake increased adipogenesis and white adipose tissue mass, which resulted in ectopic fat accumulation. Also, there was an increase of triglyceride content because fructose consumption upregulated the level of lipogenesis,³⁴ and increased lipogenesis decreased hepatic lipid oxidation and enhanced very-low-density lipoproteins (VLDL) synthesis.³⁵ Another study showed that fructose consumption induced inflammation through regulating the synthesis of fatty acids and increasing toll-like receptor 4 expression in hepatic cells, probably leading to hepatic fibrosis.³⁶ Also, the cell number of CD1c+ CD11c+ dendritic cells was significantly increased in adipose tissue after fructose diet, while there was no difference in CD4+ T cells, CD8+ T cells, neutrophils, and adipose tissue macrophages.³⁷ The previous evidence showed that high fructose intake impaired the function of regulatory T cells.³⁸ More importantly, a rapid rise of serum uric acid after fructose ingestion could increase macrophage recruitment in adipose tissue.³⁹ Also, high-fat/fructose consumption increased the number of monocytes in spleen and thymus tissues of obesity induced premature ovarian failure.⁴⁰ In the context of cardiovascular diseases, high fructose diet not only induced inflammation, but also caused cardiac dysfunction. Emerging studies showed that excessive sugar intake induced diabetic cardiomyopathy contribute to impair diastolic dysfunction and systolic failure.^41,42 Our echocardiographic findings demonstrated that EDV, and ESV significantly increased in 60% high fructose diet mice compared with control mice or 35% fructose treated mice, but there was a significant reduction of EF% and FS%. These indicators of echocardiography showed that 60% high fructose intake could impair cardiac function, leading to heart failure.

In the present study, although 35% fructose fed adult mice unsuccessfully impaired cardiac function, the cardiac dysfunction could be induced in 60% fructose fed adult mice at 12 weeks. However, the morphology of 35% and 60% fructose fed mice heart were totally different from normal diet mice, which increased the cardiomyocytes size, and relative wall thickness, especially for apical sites. The increased cardiomyocytes and relative wall thickness could be able to explain that fructose consumption of 12 weeks induced cardiac hypertrophy, although there was no difference in the ratio of HW/BW after fructose intake compared to control mice. Also, excessive fructose intake could upregulate pro-fibrotic markers and then aggravate cardiac fibrosis.

More importantly, high fructose intake regulated the levels of uric acid and then increased the blood pressure.² Increased uric acid stimulated the inflammatory of macrophages infiltration, leading to differentiate into foam cell through oxidative stress and xanthine oxidase in atherosclerosis, and also uric acid promoted the production of inflammatory cytokines secreted by these foam cells or macrophages.⁴³ Also, MCP-1 expression was upregulated in adipose tissue and renal tissue after fructose stimulation.^16,44 Macrophages are key mediators for heart regeneration and repair, and MCP-1/CCR-2 signaling could promote macrophages infiltration in injured site to improve cardiac function after injury. Our previous findings also demonstrated that recruited M1-like macrophages contribute to clear dead cells or tissue, resulting in inhibiting pro-inflammatory cytokines production and subsequently suppressing cardiac hypertrophy after heart injury.³² However, macrophage could result in diastolic dysfunction in high-fat fed adult mice.⁴⁵ Patients with fructose feeding would increase CD11c+ expression of monocytes cells from blood, which promoted atherogenesis and myocardial infarction.⁴⁶ Thus, we tested the expression level of MCP-1 in adult heart after fructose stimulation. Our findings demonstrated that mRNA and protein levels of MCP-1 of HL-1 cell lines and isolated primary CM was significantly induced in fructose-dose dependent manner. Also, there was a significant increased MCP-1 expression in 60% high-fructose treated adult mice, which consequently promoted the production of pro-inflammatory genes (IL-6, TNF-α, and COX-2) and cell adhesion molecules (ICAM-1, and VCAM-1). Surprisedly, we also observed macrophage infiltration in high fructose fed mice.

Taken together, our results demonstrated that high-fructose diet could induce cardiac dysfunction in adult mice. It is possible high-fructose intake daily could promote MCP-1expression, leading to macrophage recruitment and inflammatory response. More evidences are needed to investigate the potential function of high-fructose upregulated MCP-1 expression, such as signaling pathways and inflammatory mechanisms, underlying cardiac hypertrophy and fibrosis.

Supplemental Material

Supplemental Material, sj-docx-1-cpt-10.1177_10742484231162249 - High-Fructose Diet Induces Cardiac Dysfunction via Macrophage Recruitment in Adult Mice

Supplemental Material, sj-docx-1-cpt-10.1177_10742484231162249 for High-Fructose Diet Induces Cardiac Dysfunction via Macrophage Recruitment in Adult Mice by Xiao Wang, Zuqing Xu, Rong Chang, Changchun Zeng and Yanli Zhao in Journal of Cardiovascular Pharmacology and Therapeutics

Footnotes

Authors’ Note

The care of laboratory animal and the animal experimental operations were approved by the Ethics Review Committee of Guangdong Medical University(ID number: GDY2002022) according to Administration Rule of Laboratory Animal. Requests for materials and reagents should be address to the correspondence author.

Acknowledgments

We thank Mrs Yuanyuan Wang, Mrs Sijing Huang, and Mr Guochuan Wu for technical help in blindly taking animal samples.

Author Contributions

Xiao Wang, Zuqing Xu, Rong Chang, and Yanli Zhao contributed equally to this work and share first authorship. Xiao Wang, Zuqing Xu, and Yanli Zhao performed experiments and analyzed the data; Yanli Zhao, Rong Chang, and Changchun Zeng contributed to reagents and machinery support; Yanli Zhao designed, wrote, and corrected the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen, China (Grant/Award Number: 2020162), Shenzhen Longhua District key laboratory of infection and immunity project and Department of medical laboratory platform from Shenzhen Longhua District Central Hospital.

ORCID iD

Yanli Zhao

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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