CXCR4-dependent macrophage-to-fibroblast signaling contributes to cardiac diastolic dysfunction in heart failure with preserved ejection fraction

Abstract

Rationale: Heart failure with preserved ejection fraction (HFpEF) can arise from hypertension-induced cardiac remodeling. Monocyte/macrophage accumulation and inflammation are crucial elements in the pathogenesis of hypertension-induced cardiac remodeling. The C-X-C chemokine receptor 4 (CXCR4) is a critical regulator of the macrophage-mediated immune response. Nevertheless, the contribution of CXCR4 to macrophage phenotype and function during the progression of HFpEF remains unclear. Herein, we aimed to determine the role of macrophagic CXCR4 in heart failure with preserved ejection fraction (HFpEF). Methods: As a HFpEF model, wild type mice and myeloid-specific CXCR4 deficiency mice were subjected to pressure overload for 30 days to assess the function of macrophagic CXCR4 on cardiac function. Medium from macrophages was used to treat cardiac fibroblasts to study macrophage-to-fibroblast signaling. Results: We found circulatory CXCR4+ immune cells, mainly monocytes, markedly increased in HFpEF patients with hypertension. In the experimental HFpEF mice model, macrophages but not neutrophils represent the main infiltrating inflammatory cells in the heart, abundantly expressing CXCR4. Myeloid-specific CXCR4 deficient impeded macrophage infiltration and inflammatory response in the heart of HFpEF mice, thus ameliorating cardiac fibrosis and improving cardiac diastolic function. Furthermore, transcriptomic profiling data revealed that CXCR4 loss in macrophages exhibited a decreased transcriptional signature associated with the regulation of inflammatory response. Notably, CXCR4 significantly augmented chemokine (C-X-C) motif ligand (CXCL3) expression, which at least partly contributed to fibrosis by promoting myofibroblast differentiation. Mechanistically, the increased production of pro-inflammatory cytokines in CXCR4 expressed macrophages could be attributed to the suppression of the peroxisome proliferator-activated receptor γ (PPARγ) activity. Conclusions: Collectively, our data supported that the infiltration of CXCR4+ macrophages in the heart exacerbates hypertension-induced diastolic function by promoting pro-inflammatory cytokines production and thus may serve as a potential therapeutic target for hypertension-induced HFpEF.

Heart failure with preserved ejection fraction and non‐alcoholic fatty liver disease: new insights from bioinformatics

“…For instance, in an HFpEF mouse model constructed by salty drinking water/unilateral nephrectomy/aldosterone or macrophages, major infiltrating inflammatory cells in the heart expressed CXCR4 in large numbers. The high expression of CXCR4 can inhibit peroxisome proliferator‐activated receptor γ activity, enhance the pro‐inflammatory state of macrophages, and also fuel CXCL3 expression to promote myofibroblast differentiation and fibrosis 35 . Inhibition of the C‐C motif chemokine ligand (CCL)2/C‐C motif chemokine receptor (CCR)2 axis can improve cardiac dysfunction and delay fibrosis in the TAC mouse model 36 .…”

Feline myocardial transcriptome in health and in hypertrophic cardiomyopathy—A translational animal model for human disease

“…CXCR4 is a chemokine receptor that is expressed in cardiomyocytes, fibroblasts and endothelial cells, mediates homing of progenitor cells, is involved in cell proliferation, migration and survival; and has been identified as a hub gene in human HCM [26,71,72,75,76]. In a mouse model of heart failure with preserved ejection fraction, increased CXCR4-positive macrophages were found in the circulation and the myocardium, which was associated with myofibroblast differentiation, fibrosis and an increased in inflammatory cytokines [77]. The gene expression for the chemokines MIF and CXCL12, which are the main CXCR4 ligands, were reduced in the HCM LV.…”

Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction: What are the Experimental Proofs?

“…Alternatively, cardiac fibrosis was proposed to be favored by EC activation, which subsequently led to inflammatory cells infiltration in the heart. Both macrophage-derived Interleukin-10 (IL-10) (Zhang N. et al, 2022) and T-cell derived Interleukin-18 (IL-18) (Yu et al, 2009) were shown to promote cardiac fibroblast activation. Besides, lymphocytes were shown to be necessary for cardiac fibrosis and diastolic dysfunction (increased EDP) in HFD-fed mice using SCID mice (Zibadi et al, 2010).…”

“…Macrophages via Il-10 production (Zhang N. et al, 2022) and neutrophils via neutrophil extracellular traps (NETs) (Zhang X.-L. et al, 2022) were shown to promote diastolic dysfunction (increased EDP and Tau) in a mouse model of hypertension induced by salty drinking water, unilateral nephrectomy, and chronic exposure to aldosterone. We have shown that mast cells via histamine release promote diastolic dysfunction (increased EDP) in Lerp db/db mice (Guimbal et al, 2021).…”

“…Altogether these results demonstrate that EC activation, by promoting inflammatory cells recruitment may participate in the pathophysiology of HF since many inflammatory chemokines were shown to have detrimental effects on cardiac function. Notably, neither macrophages via Il-10 nor mast cells via histamine did participate in the development of cardiac hypertrophy (Guimbal et al, 2021;Zhang N. et al, 2022).…”