scholarly journals S100A9 is a functional effector of infarct wall thinning after myocardial infarction

2021 ◽  
Author(s):  
Upendra Chalise ◽  
Mediha Becirovic-Agic ◽  
Michael J Daseke II ◽  
Shelby R. Konfrst ◽  
Jocelyn R. Rodriguez-Paar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Neutrophil Infiltration ◽  
Vehicle Control ◽  
Macrophage Infiltration ◽  
Secreted Protein ◽  
Cardiac Physiology ◽  
Wall Thinning ◽  
Saline Vehicle ◽  
Lower Ejection Fraction

Neutrophils infiltrate into the left ventricle (LV) early after myocardial infarction (MI) and launch a pro-inflammatory response. Along with neutrophil infiltration, LV wall thinning due to cardiomyocyte necrosis also peaks at day 1 in the mouse model of MI. To understand the correlation, we examined a previously published dataset that included day 0 (n=10) and MI day 1 (n=10) neutrophil proteome and echocardiography assessments. Out of 123 proteins, 4 proteins positively correlated with the infarct wall thinning index (1/wall thickness): histone 1.2 (r=0.62, p=0.004), S100A9 (r=0.60, p=0.005), histone 3.1 (r=0.55, p=0.01), and fibrinogen (r=0.47, p=0.04). As S100A9 was the highest ranked secreted protein, we hypothesized that S100A9 is a functional effector of infarct wall thinning. We exogenously administered S100A8/A9 at the time of MI to mice (C57BL/6J, male, 3-6 months of age, n=7M (D1), and n=5M (D3)) and compared to saline vehicle control treated mice (n=6M (D1) and n=6M (D3)) at MI days 1 and 3. At MI day 3, the S100A8/A9 group showed a 22% increase in the wall thinning index compared to saline (p=0.02), along with higher dilation and lower ejection fraction. The decline in cardiac physiology occurred subsequent to increased neutrophil and macrophage infiltration at MI day 1 and increased macrophage infiltration at D3. Our results reveal that S100A9 is a functional effector of infarct wall thinning.

scholarly journals Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization

2015 ◽  
Vol 308 (12) ◽  
pp. C972-C982 ◽  
Author(s):  
Hiroe Toba ◽  
Lisandra E. de Castro Brás ◽  
Catalin F. Baicu ◽  
Michael R. Zile ◽  
Merry L. Lindsey ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Gene Array ◽  
Peritoneal Macrophages ◽  
Macrophage Infiltration ◽  
Secreted Protein ◽  
Middle Aged ◽  
Cardiac Inflammation ◽  
Age Related

To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in age-related cardiac inflammation, we studied six groups of mice: young (3–5 mo old), middle-aged (10–12 mo old), and old (18–29 mo old) C57BL/6 wild-type (WT) and SPARC-null (Null) mice ( n = 7–10/group). Cardiac function and structure were determined by echocardiography. The left ventricle was used for cytokine gene array and macrophage quantification by immunohistochemistry. Macrophage infiltration increased with age in WT ( n = 5–6/group, P < 0.05 for young vs. old), but not in Null. Proinflammatory markers ( Ccl5, Cx3cl1, Ccr2, and Cxcr3) increased in middle-aged and old WT, whereas they were increased only in old Null compared with respective young ( n = 5–6/group, P < 0.05 for all). These results suggest that SPARC deletion delayed age-related cardiac inflammation. To further assess how SPARC affects inflammation, we stimulated peritoneal macrophages with SPARC ( n = 4). SPARC treatment increased expression of proinflammatory macrophage M1 markers and decreased anti-inflammatory M2 markers. Echocardiography ( n = 7–10/group) revealed an age-related increase in wall thickness of the left ventricle in WT (0.76 ± 0.02 mm in young vs. 0.91 ± 0.03 mm in old; P < 0.05) but not in Null (0.78 ± 0.01 mm in young vs. 0.84 ± 0.02 mm in old). In conclusion, SPARC deletion delayed age-related increases in macrophage infiltration and proinflammatory cytokine expression in vivo and in vitro. SPARC acts as an important mediator of age-related cardiac inflammation by increasing the expression of macrophage M1 markers and decreasing M2 markers.

PHENOTYPIC HETEROGENEITY OF CARDIAC MACROPHAGES DURING WOUND HEALING FOLLOWING MYOCARDIAL INFARCTION: PERSPECTIVES IN CLINICAL RESEARCH

2018 ◽  
Vol 33 (2) ◽  
pp. 70-76 ◽  
Author(s):  
A. E. Gombozhapova ◽  
Yu. V. Rogovskaya ◽  
M. S. Rebenkova ◽  
J. G. Kzhyshkowska ◽  
V. V. Ryabov
Keyword(s):  
Myocardial Infarction ◽  
Wound Healing ◽  
Cardiac Remodeling ◽  
Phenotypic Heterogeneity ◽  
Macrophage Infiltration ◽  
Myocardial Regeneration ◽  
Control Group ◽  
M2 Macrophage ◽  
Inflammatory Phase ◽  
Regenerative Phase

Purpose. Myocardial regeneration is one of the most ambitious goals in prevention of adverse cardiac remodeling. Macrophages play a key role in transition from inflammatory to regenerative phase during wound healing following myocardial infarction (MI). We have accumulated data on macrophage properties ex vivo and in cell culture. However, there is no clear information about phenotypic heterogeneity of cardiac macrophages in patients with MI. The purpose of the project was to assess cardiac macrophage infiltration during wound healing following myocardial infarction in clinical settings taking into consideration experimental knowledge.Material and Methods. The study included 41 patients with fatal MI type 1. In addition to routine analysis, macrophages infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage, while CD163, CD206, and stabilin-1 were considered as M2 macrophage biomarkers. Nine patients who died from noncardiovascular causes comprised the control group.Results. The intensity of cardiac macrophage infiltration was higher during the regenerative phase than during the inflammatory phase. Results of immunohistochemical analysis demonstrated the presence of phenotypic heterogeneity of cardiac macrophages in patients with MI. We noticed that numbers of CD68+, CD163+, CD206+, and stabilin-1+ macrophages depended on MI phase.Conclusion. Our study supports prospects for implementation of macrophage phenotyping in clinic practice. Improved understanding of phenotypic heterogeneity might become the basis of a method to predict adverse cardiac remodeling and the first step in developing myocardial regeneration target therapy.

Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

2021 ◽  
pp. 107424842198957
Author(s):  
Yuting Tang ◽  
Xiaofang Lin ◽  
Cheng Chen ◽  
Zhongyi Tong ◽  
Hui Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Early Phase ◽  
Heart Function ◽  
Macrophage Polarization ◽  
Late Phase ◽  
Macrophage Infiltration ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization ◽  
Nucleolin Expression

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

scholarly journals The Use of Artificial Hypoxia in Endurance Training in Patients after Myocardial Infarction

2021 ◽  
Vol 18 (4) ◽  
pp. 1633 ◽  
Author(s):  
Agata Nowak-Lis ◽  
Tomasz Gabryś ◽  
Zbigniew Nowak ◽  
Paweł Jastrzębski ◽  
Urszula Szmatlan-Gabryś ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Endurance Training ◽  
Exercise Tolerance ◽  
Collateral Circulation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Test Duration ◽  
Hemodynamic Parameters ◽  
Ventricular Ejection Fraction

The presence of a well-developed collateral circulation in the area of the artery responsible for the infarction improves the prognosis of patients and leads to a smaller area of infarction. One of the factors influencing the formation of collateral circulation is hypoxia, which induces angiogenesis and arteriogenesis, which in turn cause the formation of new vessels. The aim of this study was to assess the effect of endurance training conducted under normobaric hypoxia in patients after myocardial infarction at the level of exercise tolerance and hemodynamic parameters of the left ventricle. Thirty-five patients aged 43–74 (60.48 ± 4.36) years who underwent angioplasty with stent implantation were examined. The program included 21 training units lasting about 90 min. A statistically significant improvement in exercise tolerance assessed with the cardiopulmonary exercise test (CPET) was observed: test duration (p < 0.001), distance covered (p < 0.001), HRmax (p = 0.039), maximal systolic blood pressure (SBPmax) (p = 0.044), peak minute ventilation (VE) (p = 0.004) and breathing frequency (BF) (p = 0.044). Favorable changes in left ventricular hemodynamic parameters were found for left ventricular end-diastolic dimension LVEDD (p = 0.002), left ventricular end-systolic dimension LVESD (p = 0.015), left ventricular ejection fraction (LVEF) (p = 0.021), lateral e’ (p < 0.001), septal e’ (p = 0.001), and E/A (p = 0.047). Endurance training conducted in hypoxic conditions has a positive effect on exercise tolerance and the hemodynamic indicators of the left ventricle.

Injection of a novel synthetic hydrogel preserves left ventricle function after myocardial infarction

2009 ◽  
Vol 90A (2) ◽  
pp. 472-477 ◽  
Author(s):  
Xue-Jun Jiang ◽  
Tao Wang ◽  
Xiao-Yan Li ◽  
De-Qun Wu ◽  
Zhao-Bin Zheng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Left Ventricle Function ◽  
Synthetic Hydrogel ◽  
Ventricle Function

scholarly journals TMIC-24. COLONY STIMULATING FACTOR 1 INHIBITION DECREASES TUMOR GROWTH AND MACROPHAGE INFILTRATION, AND INCREASES NEUTROPHIL INFILTRATION IN XENOGRAFT MICE MODELS OF GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi252-vi252
Author(s):  
Sabbir Khan ◽  
Yuji Piao ◽  
Sandeep Mittal ◽  
Kain McGee ◽  
Soon Park ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Myeloid Cell ◽  
Neutrophil Infiltration ◽  
Macrophage Infiltration ◽  
Colony Stimulating Factor ◽  
Vegf Inhibitors ◽  
Mesenchymal Transition ◽  
Vegf Inhibition ◽  
Stimulating Factor

Abstract Glioblastoma (GBM) is the most common, highly aggressive and lethal primary brain tumor in adults, and has a median overall survival ranging from 12 to 15 months. Several human cancers including glioma are infiltrated with numerous immune cell types which play a critical role in tumor growth, invasion and resistance to treatment. Previous studies, including our group, have shown that resistance to anti-VEGF therapy is associated with myeloid cell infiltration and mesenchymal transition in GBM. Notably, most glioma patients have shown increase in CD68+ cells due to overproduction of colony stimulating factor 1 (CSF-1) by tumor cells, a growth factor for macrophages. Therefore, we hypothesized that CSF-1 inhibition may reduce macrophage and/or myeloid cell infiltration in glioma, thereby increasing animal survival as monotherapy or in combination with VEGF inhibitors in xenograft GBM mouse models. We tested two CSF-1R inhibitors (AZD 7507 and JNJ-28312141) alone and in combination with VEGF inhibition to prevent macrophage infiltration in xenograft GBM mouse models. CSF-1R and VEGF inhibitors reduced macrophage infiltration (F4/80 staining), tumor volume, and mesenchymal transition (YKL-40 staining), and there was a marginal survival benefit in this model. Interestingly, despite significant reduction in tumor macrophages, we observed a significant increase in neutrophil infiltration and hypoxia (HIF1α staining), particularly in the combinatorial treated. Considering these observations, we further evaluated tumor-associated neutrophil (TAN) infiltration in GBM patient tumors by fluorescence-activated cell sorting (FACS). FACS-isolated TANs were identified as CD11b+/CD15+/CD66b+ triple positive. Our results shown that the infiltrating TAN population vary from 0.5 to 5% in GBM patient tumors. Detailed characterization of TAN population and polarization in patient tumors are ongoing. Our findings revealed that CSF-1 and VEGF inhibition reduced macrophage infiltration and tumor growth, but significantly increased TAN infiltration which will likely hamper the potential therapeutic benefit of anti-CSF1-directed inhibitors.

Abstract 12: EMMPRIN-Targeted Magnetic Nanoparticles for in vivo Visualization and Regression of Acute Myocardial Infarction in a Model of Acute Coronary Artery Occlusion

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Irene Cuadrado ◽  
Maria Jose Garcia Miguel ◽  
Irene Herruzo ◽  
Mari Carmen Turpin ◽  
Ana Martin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Extracellular Matrix ◽  
Coronary Artery ◽  
Left Ventricle ◽  
Infarct Size ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Gadolinium Enhancement

Extracellular matrix metalloproteinase inducer EMMPRIN, is highly expressed in patients with acute myocardial infarction (AMI), and induces activation of several matrix metalloproteinases (MMPs), including MMP-9 and MMP-13. To prevent Extracellular matrix degradation and cardiac cell death we targeted EMMPRIN with paramagnetic/fluorescent micellar nanoparticles with an EMMPRIN binding peptide AP9 conjugated (NAP9), or an AP9 scramble peptide as a negative control (NAPSC). NAP9 binds to endogenous EMMPRIN as detected by confocal microscopy of cardiac myocytes and macrophages incubated with NAP and NAPSC in vitro, and in vivo in mouse hearts subjected to left anterior descending coronary artery occlusion (IV injection 50mγ/Kg NAP9 or NAP9SC). Administration of NAP9 at the same time or 1 hour after AMI reduced infarct size over a 20% respect to untreated and NAPSC injected mice, recovered left ventricle ejection fraction (LVEF) similar to healthy controls, and reduced EMMPRIN downstream MMP9 expression. In magnetic resonance scans of mouse hearts 2 days after AMI and injected with NAP9, we detected a significant gadolinium enhancement in the left ventricle respect to non-injected mice and to mice injected with NAPSC. Late gadolinium enhancement assays exhibited NAP9-mediated left ventricle signal enhancement as early as 30 minutes after nanoprobe injection, in which a close correlation between the MRI signal enhancement and left ventricle infarct size was detected. Taken together, these results point EMMPRIN targeted nanoprobes as a new tool for the treatment of AMI.

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