As the global incidence of heart failure (HF) continues to rise, accompanied by an increasing hospitalization and mortality rate among HF patients, it has emerged as a substantial public health concern[15, 16]. Traditional biomarkers for heart failure, such as BNP or NTproBNP, carry significant diagnostic and prognostic value for both acute and chronic HF, and they are widely integrated into clinical practice. However, their specificity remains constrained. In conditions like pneumonia, asthma, pulmonary embolism, and interstitial lung disease, BNP or NT-proBNP levels can also exhibit a certain degree of elevation[17]. This presents challenges when diagnosing heart failure. Thus, delving into the exploration and identification of more precise HF biomarkers offers the potential for early screening and diagnosis of heart failure. This endeavor not only illuminates the initial dysregulation and underlying mechanisms of the disease but also addresses a pressing challenge in current research.
With the progression of sequencing technologies, the application of bioinformatics analysis has become widespread, facilitating the revelation of interactions between gene expression characteristics and diseases. Numerous studies have underscored that excessive inflammation and malfunctioning immune cells play substantial roles in the pathogenesis of HF[18]. Consequently, investigating the distribution of immune cells in HF and their associated gene profiles holds substantial importance in the development of novel HF diagnostic markers and targeted therapies.
This study analyzed the distribution and quantity of 22 immune cell types in HF, revealing a reduction in monocyte count.
Monocytes, the largest blood cells, and a key component of the body's defense system play a vital role[19, 20]. Inflammatory cells in the human body possess reactive factors, regulated by monocytes, which indicates a close association between monocyte activation and chronic inflammation in the body. When activated, monocytes release agents that incite inflammatory reactions, oxidative stress, and expedited adhesion of factors to various sites, thus catalyzing inflammation, and oxidative stress, ultimately leading to harm. In cases of dysfunctional myocardial endothelium, monocytes traverse and attach to blood vessel walls, amassing within the cardiovascular intima, where they transition into macrophages[21, 22]. Utilizing scavenger receptors SR-A and CD-36, they engulf oxidatively modified low-density lipoprotein (ox-LDL) and other lipid types, differentiating into foam cells. These foam cells secrete tissue factors, pro-inflammatory cytokines, and matrix metalloproteinases, thereby amplifying the inflammatory response in the myocardial region and hastening the damage to myocardial cells. Furthermore, post-transformation macrophages facilitate the conversion of fibroblasts into myofibroblasts, leading to abundant collagen synthesis. Concurrently, their secreted proteases undermine the extracellular matrix, remodeling tissue and giving rise to myocardial scars [23]. In a distinct aspect, inflammatory responses can influence the body's coagulation function, provoking an augmentation in procoagulant factor release. In a resting state, monocytes bolster the synthesis of thermoregulatory proteins and express surface cytokines, leading to elevated thrombosis and enhanced coagulation[24]. The research underscores that heightened surface cytokine expression on monocytes not only amplifies the effects but also assists cytokines in propelling other cells, thus exacerbating immune cell function impairment, myocardial injury, and ensuing cardiac remodeling and functional deterioration[25]. These studies underscore the pivotal role of monocytes in the progression of HF and suggest their potential as therapeutic targets in HF management.
Through the analysis of monocytes, clinical module genes, and differentially expressed genes, we identified four key genes associated with HF. Among them, COL14A1, COL16A1, and HTRA1 demonstrated elevated levels in HF, exhibiting a negative correlation with monocytes. On the other hand, SOS1 exhibited decreased levels in HF, showing a positive correlation with monocytes.
COL14A1 is a large extracellular matrix glycoprotein associated with collagen cell maturation. Downregulation of COL14A1 and similar fibrotic factors induces the transcription of genes involved in protective cardiac wound healing, exerting a negative regulation on adverse myocardial remodeling[26].The COL16A1 gene encodes the α chain of type XVI collagen, contributing to the maintenance of extracellular matrix integrity. It shows a positive correlation with left ventricular dysfunction in individuals with ischemic cardiomyopathy[27]. Research suggests that elevated COL16A1 expression is evident in tissues of patients with diabetic cardiomyopathy, underscoring its role in the advancement of cardiac dilation and remodeling [28].
The serine protease HTRA1 functions as a secreted enzyme with two primary activities: it inhibits TGF-β1 signaling transduction and degrades various extracellular substrates. HTRA1 collaborates with oxidized phospholipids to enhance inflammatory responses and promote macrophage infiltration[29]. In the research conducted by D Colak and colleagues, a notable upregulation of HTRA1 was identified in dilated cardiomyopathy (DCM) with a fold increase of 6.9. This finding indicates a plausible link between HTRA1 and the underlying pathogenic processes of DCM[30]. Furthermore, in line with our own research, Zhou et al., in their analysis of the HF-associated GSE57345 dataset, identified three crucial genes, including HTRA1, that exhibited a correlation with HF prognosis [31].SOS1 functions as a guanine nucleotide exchange factor for Ras proteins. In cases of severe PM2.5 exposure, SOS1 downregulation severely impairs cardiac tissue and its functionality[32, 33]. Additionally, during the process of myocardial cell aging, treatment with fucoidan and astaxanthin leads to decreased SOS1 expression levels[34]. While certain earlier research findings correspond with our analysis, the reliability of our study's results requires further experimental validation.
In conclusion, our findings suggest that COL14A1, COL16A1, HTRA1, and SOS1 could potentially serve as diagnostic markers for HF. Simultaneously, monocytes may play a role in the onset and progression of HF. Additionally, the negative correlation of COL14A1, COL16A1, and HTRA1 with monocytes, along with the positive correlation of SOS1 with monocytes, indicates that these genes might be intricately involved in modulating monocyte function during the development of HF. Further investigation into the regulatory mechanisms of monocytes could potentially unveil immunotherapeutic targets for managing HF, thereby contributing to the refinement of immune-based treatment strategies for HF patients.