Elsevier

Pharmacological Research

Volume 141, March 2019, Pages 104-113
Pharmacological Research

Network pharmacology based investigation of the effects of herbal ingredients on the immune dysfunction in heart disease

https://doi.org/10.1016/j.phrs.2018.12.016Get rights and content

Abstract

Dysregulated immune system has been implicated in the pathogenesis of various cardiovascular diseases. Therefore, development of pharmacological interventions targeting the immune system is promising. However, therapy with most common anti-inflammatory and immunomodulatory agents has proved challenging in the clinical translation. It has been proved that many herbal ingredients display definite therapeutic effects on preventing excessive inflammatory and immune responses. Here, we aim to systemically explore the immunomodulatory ability of herbal ingredients on the human heart tissue-specific immune dysfunction through a network pharmacology based approach. The approach matches gene expression data between herbal ingredients and human heart phenotype based on their immunological similarities. Firstly, 608 immunological signatures were produced from 304 transcriptional profiles of immunological cell state changes. Then, the immunological features of 28 human heart phenotypes and 102 herbal ingredients were constructed by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients, respectively. Finally, the likelihood that an herbal drug affects the immune system in a heart phenotype was qualified by calculating the immunological similarity between the herbal drug and the heart phenotype. This strategy integrating different types of OMICs data is expected to help create new opportunities for development of drugs targeting the immune dysfunction in heart disease.

Introduction

Inflammatory processes underlying many diseases and syndromes play an important role in pathologies afflicting both the heart and the vasculature, including myocardial infarction (MI), heart failure (HF), atherosclerosis, atrial fibrillation and stroke [[1], [2], [3]]. For example, maladaptive inflammation is causally involved in the overall development of MI, in which cardiomyocyte necrosis triggers an intense inflammation and immune cell infiltration to clear the infarct from dead cells and matrix debris followed by a reparative phase with resolution of inflammation and scar formation. The abnormality of the inflammatory phase can lead to sustained tissue damage and improper healing, thereby accelerating adverse remodeling of the ventricle [4]. Despite an impressive growth in our understanding of the role of inflammatory and immune signaling in the pathogenesis of cardiopathy, this new knowledge has not yet translated into effective therapy.

Over the past decades, the broad anti-inflammatory interventions including glucocorticoids, non-steroidal anti-inflammatory drugs and immunomodulatory agents were primarily tested but associated with adverse consequences. Then, researchers turned to seek to selectively target specific injurious pro-inflammatory and immune signals, including the complement cascade, C-reactive protein, integrins and selectins, as well as specific cytokines, chemokines and the matrix metalloproteinase (MMP) system. Unfortunately, despite promising results in animal experiments, targeted therapies on specific immune pathways have produced disappointing results in clinical studies. For example, the anti-C5 antibody pexelizumab that inhibits the complement cascade failed to affect cardiogenic shock and congestive heart failure, 30 day mortality and the composite endpoint of death in patients with ST elevation myocardial infarction [5]. P-selectin inhibitor inclacumab in patients with acute coronary syndromes reduced cardiomyocyte injury but did not affect clinical outcome [6]. These translational failures can be attributed to a variety of complex reasons, such as pleiotropic inflammatory and immune mediators, temporal and spatial considerations and the pathophysiologic heterogeneity of etiology [4,7]. Besides looking for solutions to these challenges, we could explore novel therapies for the inflammatory and immune system.

Herbal medicine, as a complementary or alternative modern medical system, is characterized by multiple ingredients, which are usually used as a source of new chemical entities [8]. Herbal compounds of most types and classes influence the inflammatory and immune system but the applications of these perturbations are often overlooked. In this work, we seeks to systemically analyze the links between some common human heart phenotypes and a collection of herbal compounds based on the immune system. Our strategy is built on previous systems-level approaches that compare and integrate differential expression profiles of immunological cell states with drug perturbation profiles to map effects of drugs on the immune system [9]. Recent large-scale collaborative efforts have produced compendia of molecular profiles for both herbal ingredients [10] and immune cells [11]. Gene expression data of human heart phenotypes can be obtained from public databases such as NCBI Gene Expression Omnibus (GEO).

We integrated separately human heart phenotype data from GEO and herbal drug data from human cancer cells with gene expression data obtained from mouse immune cells (Fig.1). Our analysis constructed the immunological features for human heart phenotypes and herbal ingredients by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients. Then, we quantify the likelihood that an herbal ingredient affects the immune system. In total, we generated immunological features for 28 heart phenotypes and immunological features for 102 herbal ingredients. We studied all associations of these herbal ingredients and human heart phenotypes based on the corresponding immunological features and found 2149 significant interactions (of 2856 possible interactions). From these interactions, it is expected to help create new opportunities for development of drugs targeting immune dysfunction in heart disease.

Section snippets

Construction of immunological features for human heart phenotypes

We used immunogenomic data from the previous study that compiled a set of 304 immune cell state transitions from 221 immune cell types in the Immunological Genome Project (ImmGen) [9], a publicly available compendium of genome-wide transcriptional expression profiles for more than 250 distinct immunological cell states encompassing the innate and adaptive immune systems in mice. Based on the 304 immune cell state transitions, we defined a set of 608 immunological signatures by selecting the

Discussion

Excessive, prolonged and dysregulated Inflammatory and immune reactions have been implicated in the pathogenesis of cardiovascular diseases of all types and complications. Some clinical trials and studies in animal models have suggested the effectiveness of pharmacological interventions targeting the immune system [[19], [20], [21]]. However, even in the pathophysiological mechanisms of acute cardiac injury and fibrosis with firmly established knowledge of the role of immune responses,

Gene expression data and preprocess

The gene expression data used in this analysis were mostly obtained from the NCBI Gene Expression Omnibus (GEO) and restricted to using only microarray data. First, the human heart phenotype-induced transcriptional data were manually searched by constructing the query field “heart [Sample Source]” and assigned to human disease conditions with following restrictions: (i) both phenotype and their corresponding control condition were measured in the same tissue and the same experiment; (ii)

Authors’ contributions

PL performed experiments, analyzed data and wrote the manuscript; JC, HML and WXZ collected and analyzed data. WW and JXC designed research and supervised the work, wrote and reviewed the manuscript.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

This research was supported by National Natural Science Fund of China (No. 81522051, No. 81703945, No. 31800678) and Technology and Innovation Fund of Shanxi Agricultural University (No. 2016YJ17, No. 2017YJ40).

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