Transcriptomic and Lipidomic Mapping of Macrophages in the Hub of Chronic Beta-Adrenergic-Stimulation Unravels Hypertrophy-, Proliferation-, and Lipid Metabolism-Related Genes as Novel Potential Markers of Early Hypertrophy or Heart Failure

Abstract

Sympathetic nervous system overdrive with chronic release of catecholamines is the most important neurohormonal mechanism activated to maintain cardiac output in response to heart stress. Beta-adrenergic signaling behaves first as a compensatory pathway improving cardiac contractility and maladaptive remodeling but becomes dysfunctional leading to pathological hypertrophy and heart failure (HF). Cardiac remodeling is a complex inflammatory syndrome where macrophages play a determinant role. This study aimed at characterizing the temporal transcriptomic evolution of cardiac macrophages in mice subjected to beta-adrenergic-stimulation using RNA sequencing. Owing to a comprehensive bibliographic analysis and complementary lipidomic experiments, this study deciphers typical gene profiles in early compensated hypertrophy (ECH) versus late dilated remodeling related to HF. We uncover cardiac hypertrophy- and proliferation-related transcription programs typical of ECH or HF macrophages and identify lipid metabolism-associated and Na+ or K+ channel-related genes as markers of ECH and HF macrophages, respectively. In addition, our results substantiate the key time-dependent role of inflammatory, metabolic, and functional gene regulation in macrophages during beta-adrenergic dependent remodeling. This study provides important and novel knowledge to better understand the prevalent key role of resident macrophages in response to chronically activated beta-adrenergic signaling, an effective diagnostic and therapeutic target in failing hearts.

Early Protective Role of Inflammation in Cardiac Remodeling and Heart Failure: Focus on TNFα and Resident Macrophages

“…These plastic cells adapt their physiology in response to cardiac and systemic stimuli. They are crucial in controlling and regulating the local tissue microenvironment, the matrix, oxygen content, acidification, and other molecular components (e.g., cytokines, growth factors, and chemokines) associated with micro-environmental shifts [ 141 ]. Mφ metabolism, including lipid metabolism, not only provides energy but also greatly influences Mφ phenotype and function, for example modulating signal transduction and gene regulation [ 142 ].…”

“…We have recently performed a transcriptomic analysis comparing genes expressed by Mφ isolated from early compensated (ECH) or failing (HF) hearts [ 141 ]. Interestingly, we identified panels of hypertrophy-related genes selectively regulated in ECH Mφ ( Rcan1 , Pik3ip1 ) or HF Mφ ( Adam22 , Tet2 , Map3k2 , Sik1 ) and thus potentially associated with compensated or failing hypertrophy remodeling, respectively.…”

“…Interestingly, we identified panels of hypertrophy-related genes selectively regulated in ECH Mφ ( Rcan1 , Pik3ip1 ) or HF Mφ ( Adam22 , Tet2 , Map3k2 , Sik1 ) and thus potentially associated with compensated or failing hypertrophy remodeling, respectively. In addition, ECH Mφ were characterized by an induction of Egfr mRNA expression, whereas HF Mφ displayed upregulated Igfbp4 (insulin-like growth factor binding protein 4), a negative regulator of IGF1 signaling [ 141 ]. Such genomic or proteomic approaches may constitute the basis for future, more in-depth studies to identify important Mφ-related pathways interfering in cardiac remodeling as well as to characterize biomarkers associated with early vs. late disease progression [ 141 , 196 , 197 , 198 , 199 ].…”

“…In addition, ECH Mφ were characterized by an induction of Egfr mRNA expression, whereas HF Mφ displayed upregulated Igfbp4 (insulin-like growth factor binding protein 4), a negative regulator of IGF1 signaling [ 141 ]. Such genomic or proteomic approaches may constitute the basis for future, more in-depth studies to identify important Mφ-related pathways interfering in cardiac remodeling as well as to characterize biomarkers associated with early vs. late disease progression [ 141 , 196 , 197 , 198 , 199 ].…”

“…Recent transcriptomic and single-cell RNA sequencing studies allowed an evaluation of the progressive reprogramming of Mφ during cardiac remodeling. This led to the uncovering of potential specific properties of Mφ isolated from early adaptive vs. late failing hearts and to identify clusters of phagocytes with distinct gene expression profiles among which some are characterized by a mixed expression of pro-inflammatory and anti-inflammatory marker-genes, further emphasizing oversimplification of Mφ categorization into M 1 and M 2 cells [ 141 , 196 , 227 , 228 , 229 ]. Early adaptive resident Mφ amplified in response to β-AR stimulation were characterized by an induction of anti-inflammatory, pro-phagocytic and pro-angiogenic gene markers [ 141 ].…”