Cellular Phenotypic Transformation in Heart Failure Caused by Coronary Heart Disease and Dilated Cardiomyopathy: Delineating at Single-Cell Level

Abstract

Heart failure (HF) is known as the final manifestation of cardiovascular diseases. Although cellular heterogeneity of the heart is well understood, the phenotypic transformation of cardiac cells in progress of HF remains obscure. This study aimed to analyze phenotypic transformation of cardiac cells in HF through human single-cell RNA transcriptome profile. Here, phenotypic transformation of cardiomyocytes (CMs), endothelial cells (ECs), and fibroblasts was identified by data analysis and animal experiments. Abnormal myosin subunits including the decrease in Myosin Heavy Chain 6, Myosin Light Chain 7 and the increase in Myosin Heavy Chain 7 were found in CMs. Two disease phenotypes of ECs named inflammatory ECs and muscularized ECs were identified. In addition, myofibroblast was increased in HF and highly associated with abnormal extracellular matrix. Our study proposed an integrated map of phenotypic transformation of cardiac cells and highlighted the intercellular communication in HF. This detailed definition of cellular transformation will facilitate cell-based mapping of novel interventional targets for the treatment of HF.

TFRC in cardiomyocytes promotes macrophage infiltration and activation during the process of heart failure through regulating Ccl2 expression mediated by hypoxia inducible factor‐1α

“…2.1 | Single-cell RNA sequencing (scRNA-seq) analysis scRNA-seq data from heart tissues of TAC-model mice was obtained from the Gene Expression Omnibus (GEO) database (GSE120064), and was analyzed with R package Seurat as previously described. 19,23…”

“…Heart‐resident macrophages are activated into pro‐inflammatory M1 type to trigger inflammatory response, resulting in accelerated deterioration of cardiac function in HF 11,12,17 . Cardiac fibroblasts are activated to trigger myocardial fibrosis in HF 18,19 . Single‐cell RNA sequencing of pressure overload‐induced pathological cardiac hypertrophy in mice showed that macrophage activation and subtype switching, a key event at middle‐stage of cardiac hypertrophy 20 .…”

“… 11 , 12 , 17 Cardiac fibroblasts are activated to trigger myocardial fibrosis in HF. 18 , 19 Single‐cell RNA sequencing of pressure overload‐induced pathological cardiac hypertrophy in mice showed that macrophage activation and subtype switching, a key event at middle‐stage of cardiac hypertrophy. 20 Targeting macrophages in hypertrophy during the switch from normal to reduced cardiac function may attenuate disease progression.…”

Exercise improves cardiac fibrosis by stimulating the release of endothelial progenitor cell-derived exosomes and upregulating miR-126 expression

“…Furthermore, it can result in diminished cardiac compliance, necrosis of cardiomyocytes, and cardiac remodeling, ultimately leading to impaired myocardial contractility and cardiac dysfunction. These pathological changes serve as crucial links between hypertension, coronary heart disease, diabetes, and the development of heart failure (10)(11)(12). Cardiac fibroblasts represent the predominant population of mesenchymal cells within the cardiac tissue.…”