Abstract
We recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early β-adrenergic stimulation. Here we characterized macrophages (Mφ) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and Mφ-depletion experiments evidenced a transient increase in Mφ number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized Mφ-enriched CD45+ cells from ECH hearts as CX3CL1- and TNFα-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1−/− knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH Mφ proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNFα. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting Mφ and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF.
Highlights
Hemodynamic cardiac stimulation initially induces early hypertrophy, a compensatory response to reduce parietal stress and prevent dysfunction
Our results demonstrate that the β-adrenergic-induced early concentric hypertrophy (ECH) heart exhibits a selective transient increase in Mφ as compared to control and heart failure (HF) hearts, with a Mφ number correlating with ECH intensity
Based on systematic echocardiographic analyses, our study provides a detailed characterization of iso-induced ECH myeloid cells using a combination of flow cytometry, tissue immunostaining, transcriptomic and secretomic approaches
Summary
Hemodynamic cardiac stimulation initially induces early hypertrophy, a compensatory response to reduce parietal stress and prevent dysfunction. The activation of the sympathetic nervous system plays a determinant role throughout cardiac r emodeling[2,3,4] but the mechanisms underlying the transition from early hypertrophy to HF are poorly understood. In addition to cardiomyocyte hypertrophy, cardiac hypertrophic remodeling is associated with determinant changes of non-myocyte cardiac cell types, including myeloid cells[7]. Our recent results suggest a novel protective paracrine impact of cardiac myeloid CD11b/c cells leading to early hypertrophy and improved resistance to oxidative s tress[15]. Transcriptomic, and secretomic analysis approaches, the aim of the present study was to isolate and characterize Mφ selectively amplified in early hypertrophy as compared to control and HF hearts, in order to better define their protective mechanism of action. We identify the cardiac CX3CL1/CX3CR1 axis as a protective signaling pathway in early hypertrophy and the potential participation of CX3CL1-secreting Mφ, transiently amplified in ECH hearts, to delay HF
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