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Background: A high-fat diet (HFD) contributes to various metabolic disorders and obesity, which are major contributors to cardiovascular disease. As an essential regulator for heart homeostasis, cardiac resident macrophages may go awry and contribute to cardiac pathophysiology upon HFD. Thus, to better understand how HFD induced cardiac dysfunction, this study intends to explore the transcriptional and functional changes in cardiac resident macrophages of HFD mice., Methods: C57BL/6J female mice that were 6 weeks old were fed with HFD or normal chow diet (NCD) for 16 weeks. After an evaluation of cardiac functions by echocardiography, mouse hearts were harvested and cardiac resident CCR2 - macrophages were sorted, followed by Smart sequencing. Bioinformatics analysis including GO, KEGG, and GSEA analyses were employed to elucidate transcriptional and functional changes., Results: Hyperlipidemia and obesity were observed easily upon HFD. The mouse hearts also displayed more severe fibrosis and diastolic dysfunction in HFD mice. Smart sequencing and functional analysis revealed metabolic dysfunctions, especially lipid-related genes and pathways. Besides this, antigen-presentation-related gene such as Ctsf and inflammation, particularly for NF-κB signaling and complement cascades, underwent drastic changes in cardiac resident macrophages. GO cellular compartment analysis was also performed and showed specific organelle enrichment trends of the involved genes., Conclusion: Dysregulated metabolism intertwines with inflammation in cardiac resident macrophages upon HFD feeding in mice, and further research on crosstalk among organelles could shed more light on potential mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Liu, Xia, Wang, Du, Wu, Wang, Wang, Shen, Wei and Xu.)

Cardiovascular diseases are an array of age-related disorders, and accumulating evidence suggests a link between cardiac resident macrophages (CRMs) and the age-related disorders. However, how does CRMs alter with aging remains elusive. In the present study, aged mice (20 months old) have been employed to check for their cardiac structural and functional alterations, and the changes in the proportion of CRM subsets as well, followed by sorting of CRMs, including C-C Motif Chemokine Receptor 2 (CCR2) + and CCR2 - CRMs, which were subjected to Smart-Seq. Integrated analysis of the Smart-Seq data with three publicly available single-cell RNA-seq datasets revealed that inflammatory genes were drastic upregulated for both CCR2 + and CCR2 - CRMs with aging, but genes germane to wound healing were downregulated for CCR2 - CRMs, suggesting the differential functions of these two subsets. More importantly, inflammatory genes involved in damage sensing, complement cascades, and phagocytosis were largely upregulated in CCR2 - CRMs, implying the imbalance of inflammatory response upon aging. Our work provides a comprehensive framework and transcriptional resource for assessing the impact of aging on CRMs with a potential for further understanding cardiac aging., (© 2024. The Author(s).)