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Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.

ABSTRACT: Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear.This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation.Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C(high) monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2(-/-) mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05).Myocardial failure is influenced by an altered myeloid cell repertoire.

SUBMITTER: Sager HB

PROVIDER: S-EPMC5378496 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.

Sager Hendrik B HB Hulsmans Maarten M Lavine Kory J KJ Moreira Marina B MB Heidt Timo T Courties Gabriel G Sun Yuan Y Iwamoto Yoshiko Y Tricot Benoit B Khan Omar F OF Dahlman James E JE Borodovsky Anna A Fitzgerald Kevin K Anderson Daniel G DG Weissleder Ralph R Libby Peter P Swirski Filip K FK Nahrendorf Matthias M

Circulation research 20160721 7

<h4>Rationale</h4>Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear.<h4>Objective</h4>This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation.<h4>Methods and results</h4>Eig ...[more]

PMID: 27444755

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Project description:The imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems results in macromolecular damage and disruption of cellular redox signaling, affecting cardiac structure and function, thus contributing to contractile dysfunction, myocardial hypertrophy, and fibrosis in chronic heart failure [chronic heart failure (CHF)]. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is an important antioxidant defense mechanism and is closely associated with oxidative stress-mediated cardiac remodeling in CHF. In the present study, we investigated the regulation of myocardial Nrf2 in the postmyocardial infarction (post-MI) state. Six weeks post-MI, Nrf2 protein was downregulated in the heart, resulting in a decrease of Nrf2-targeted antioxidant enzymes, whereas paradoxically the transcription of Nrf2 was increased, suggesting that translational inhibition of Nrf2 may contribute to the dysregulation in CHF. We therefore hypothesized that microRNAs may be involved in the translational repression of Nrf2 mRNA in the setting of CHF. Using quantitative real-time PCR analysis, we found that three microRNAs, including microRNA-27a, microRNA-28-3p, and microRNA-34a, were highly expressed in the left ventricle of infarcted hearts compared with other organs. Furthermore, in vitro analysis revealed that cultured cardiac myocytes and fibroblasts expressed these three microRNAs in response to TNF-? stimulation. These microRNAs were preferentially incorporated into exosomes and secreted into the extracellular space in which microRNA-enriched exosomes mediated intercellular communication and Nrf2 dysregulation. Taken together, these results suggest that increased local microRNAs induced by MI may contribute to oxidative stress by the inhibition of Nrf2 translation in CHF. NEW & NOTEWORTHY The results of this work provide a novel mechanism mediated by microRNA-enriched exosomes, contributing to the nuclear factor erythroid 2-related factor 2 dysregulation and subsequent oxidative stress. Importantly, these new findings will provide a promising strategy to improve the therapeutic efficacy through targeting nuclear factor erythroid 2-related factor 2-related microRNAs in the chronic heart failure state, which show potentially clinical applications.

Project description:BACKGROUND:During the progression of chronic heart failure (CHF), decreased cardiac functioning is often associated with congestion in the inferior vena vein, which in turn induces splenomegaly and subsequent hypersplenism. Hypersplenism has been shown to exacerbate endothelial dysfunction and adverse cardiac remodeling in HF mice. However, it is unknown whether this effect also occurs in CHF patients with hypersplenism. Here, we compared different patterns of myocardial remodeling between patients with and without hypersplenism. METHODS:33 CHF patients with hypersplenism were selected and carefully examined. Clinical data and baseline hemogram measurements were included in the evaluation. Another 35 CHF patients were randomly chosen as controls. All patients received formal HF treatment to ameliorate their symptoms and to preserve heart structure and functioning. Peripheral blood-derived endothelial progenitor cells (EPCs) were cultured, and the experimenters were blinded to the patients' clinical characteristics. The biological properties of the cells were then compared. The groups were also compared in terms of the free plasma hemoglobin and heme levels, endothelial adhesion molecule expression, left ventricular ejection fraction (LvEF) and cardiovascular events (re-PCI, re-myocardial infarction, stent thrombosis, stroke and death due to cardiovascular or vascular causes). RESULTS:The free plasma hemoglobin and heme levels were significantly higher in the CHF patients with hypersplenism compared with the controls (P<0.001). Additionally, the CHF patients with hypersplenism had increased levels of VCAM-1, ICAM-1, P-selectin and E-selectin (P<0.001). Echocardiography revealed a significant reduction in the LVEF in these patients compared with the controls at the 24(th) month (P=0.013). During a mean follow-up period of 24±1 months, cardiovascular events were observed in 16 patients in the CHF with hypersplenism group and 9 patients in the control group. Univariate Kaplan-Meier analysis further revealed a significant difference between the groups (P=0.021). The mRNA levels of endothelial NO synthase enzyme (eNOS) in EPCs from the CHF patients with hypersplenism were significantly lower than those in the control subjects (P<0.001). We also observed decreased proliferation potential of EPCs from the CHF patients with hypersplenism (P<0.001). Further, a significant increase in TUNEL(+) EPCs was observed in the CHF patients with hypersplenism after 6 h of stimulated ischemia compared with the control subjects (P<0.001). CONCLUSIONS:CHF patients with hypersplenism are susceptible to myocardial remodeling. Increased oxidative stress and endothelial dysfunction caused by excess free plasma hemoglobin and heme may partially explain this causality.

Dataset Information

Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.

Publications

Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.

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