Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Abstract

Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrixdegrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.

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“…In particular, stimulation of cardiomyocytes with TNFα resulted in a negative inotropic action by alteration of calcium homeostasis or in an activation of apoptotic response by binding of TNFα to TNF receptor I (TNFRI) [ [33] , [34] , [35] ]. Moreover, the chronic stimulation of cardiac fibroblast with TNFα can destroy the balance among the synthesis and the release of matrix metalloproteinase and their inhibitors carried out to extracellular matrix (ECM) degradation and cardiac remodeling [ [33] , [34] , [35] , [36] ]. Moreover, the pro-inflammatory cytokine IL-1 β demonstrated a negative inotropic effect much stronger than TNFα alteration of calcium homeostasis and destruction of the β-adrenergic receptor [ 36 ].…”

“…Moreover, the chronic stimulation of cardiac fibroblast with TNFα can destroy the balance among the synthesis and the release of matrix metalloproteinase and their inhibitors carried out to extracellular matrix (ECM) degradation and cardiac remodeling [ [33] , [34] , [35] , [36] ]. Moreover, the pro-inflammatory cytokine IL-1 β demonstrated a negative inotropic effect much stronger than TNFα alteration of calcium homeostasis and destruction of the β-adrenergic receptor [ 36 ]. This cytokine can contribute also to apoptosis activation in cardiomyocytes and collagen synthesis in fibroblasts resulting in cardiac fibrosis [ 36 ].…”

“…Moreover, the pro-inflammatory cytokine IL-1 β demonstrated a negative inotropic effect much stronger than TNFα alteration of calcium homeostasis and destruction of the β-adrenergic receptor [ 36 ]. This cytokine can contribute also to apoptosis activation in cardiomyocytes and collagen synthesis in fibroblasts resulting in cardiac fibrosis [ 36 ]. Similarly, the exposition of cardiomyocytes to high levels of IL-6 depresses the basal contractility of the myocytes as well as the beta-adrenergic responsiveness of the cells leading to decreased heart function [ 37 ].…”

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“…Circulating levels of NT-proBNP, and also diastolic dysfunction have been reported to be increased in AA patients without clinical HF compared to control individuals without AA or other inflammatory diseases [ 15 – 18 ]. This might reflect the presence of subclinical cardiac stress and increased myocardial wall tension, which may contribute to HF progression, due to increased secretion of BNP in cardiomyocytes, induced by proinflammatory cytokines [ 19 , 20 ].…”

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“…It has been reported that atherosclerosis is a chronic vascular wall-related inflammatory disease that occurs within the arterial wall ( 2 ). Inflammatory factors are mainly divided into three categories: i) Chemokines, including monocyte chemoattractant protein-1 (MCP-1), fractalkine/CX3CR1 and macrophage colony stimulating factor, whose effects are inhibited by macrophage migration inhibition factor (MIF); ii) pro-inflammatory factors, including C-reactive protein, IL-6, IL-1 and TNF-α; and iii) anti-inflammatory factors, including IL-10 and TGF-β ( 3 ). Pharmacological studies have reported that the imbalances between the pro-atherogenic inflammatory response and atheroprotective anti-inflammatory responses serve a key role in the initiation and progression of atherosclerosis ( 4 ).…”