Editorial: Debates in cardiovascular pharmacology and drug discovery: 2022
Keman Xu1 
Fatma Saaoud1 
Ying Shao1 
Yifan Lu1 
Xiaohua Jiang1,2 
Sheng Wu2 
Jianxin Sun3 
Filipe Fernades Conti4 
Laisel Martinez4 
Roberto Vazquez-Padron4 
Hong Wang2 
Xiaofeng Yang1,2*
- 1Lemore Center for Integrated Lymphatics and Vascular Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
- 2Centers of Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
- 3Center for Translational Medicine, Vascular Biology and Therapeutics Program, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States
- 4DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, United States
Editorial on the Research Topic
Debates in cardiovascular pharmacology and drug discovery: 2022
Introduction
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. High-throughput metabolomics analysis is a powerful tool in characterizing metabolomic reprogramming related to various diseases in biomedical fields, uncovering the underlying novel metabolic mechanisms, and identifying diagnostic biomarkers (1, 2). Yet, our understanding of the metabolite-based danger-associated molecular patterns (DAMPs) (3, 4) amplified inflammation during CVDs (5) is not fully elucidated. Our Research Topic: Debates in Cardiovascular Pharmacology and Drug Discovery: 2022 at the Frontiers in Cardiovascular Medicine highlighted five papers. Those highlights encompass original research papers and reviews and provide a comprehensive view of drugs and metabolic mechanisms associated with CVDs. In 2023, we will continue to maintain an exceptional platform that fosters the exchange of groundbreaking insights among cardiologists, translational cardiovascular researchers, and experts in cardiovascular pharmacology and drug discovery.
Metabolic reprogramming and trained immunity/inflammation constitute a significant risk factor for the development of cardiovascular diseases
CVDs, for the most part, originate from disturbances in cardiovascular metabolism (6–9). Metabolites are the dynamic feedback of metabolism in cells, tissues, or organisms. They are uniquely positioned in the ‘omics’ hierarchy, representing the terminal products of processes originating from other “upstream levels” such as the genome, epigenome, transcriptome, and proteome. Metabolomics, a cutting-edge technology, has become a valuable tool for studying CVDs by revealing changes in metabolism. Comparing metabolite variations in the presence of pathophysiological conditions offers additional insights into the metabolomic mechanisms underlying the pathogenesis of diseases (2).
The development of CVDs is closely tied to inflammation pathologies. Nevertheless, the precise mechanisms through which metabolic reprogramming promotes inflammation in the context of CVD remain elusive. Earlier publications have indicated that persistent inflammatory metabolic reprogramming of innate immune cells and their bone marrow precursors plays a pivotal role in the onset and progression of CVDs (10). This metabolic reprogramming is associated with the concept of trained immunity (also termed innate immune memory) (2, 11). To be more specific, trained immunity is achieved through metabolic alterations within innate immune cells in response to stimuli. This process involves histone modifications such as methylation and acetylation, resulting in enduring epigenetic changes in inflammation-associated gene promoters and activating four metabolic pathways, including glycolysis, acetyl coenzyme A (acetyl-CoA) generation, mevalonate-cholesterol synthesis, and glutaminolysis (5). Innate immune cells that have undergone this “training” and developed stimuli-non-specific memories exhibit more robust responses when faced with the potential for re-stimulation (12).
Nevertheless, a significant question that remains is: how do different CVDs simultaneously and uniformly reprogram all four metabolic pathways? A recent publication has revealed that during early hyperlipidemia-induced atherosclerosis, three distinct types of trained immunity coexist. Each of these trained immunity types is characterized by specific mechanisms, including acetyl-CoA-cholesterol-driven histone acetylation dependence, S-adenosylhomocysteine (SAH) hypomethylation-triggered histone demethylation dependence, and glycolysis-independent metabolic pathways (2). These concurrent forms of trained immunity collectively play a pivotal role in exacerbating inflammation (13–20) and driving the progression of atherosclerosis (2, 21). In addition, this paper clearly showed that metabolomic reprogramming exhibits pronounced specificity at the tissue and subcellular organelle levels (22, 23). It is noteworthy that a significant number of upregulated metabolites are prominently expressed within the mitochondria of the heart. This underscores the elevated energy demand (24) associated with the initial stages of atherosclerosis in the cardiac tissue (2).
Five highlights of our research topic relate to therapeutic studies in metabolic reprograming, inflammation, and trained immunity
Metabolomics plays a crucial role in delineating pathophysiological responses and identifying markers for potential drug candidates. As we mentioned above, mitochondria (25) play a major role in the process of atherosclerosis, and a similar result was also reported by Xiang et al. in myocardial infarction (MI). Xiang’s group investigated a traditional Chinese medicine called Modified Linggui Zhugan Decoction (MLZD), which protects against MI by improving mitochondrial functions and reversing ventricular remodeling (26). In addition, Wu et al. examined the association of estimated pulse wave velocity with all causes and cardiovascular mortality in patients with diabetes (27). Jiang et al. comprehensively summarized the signaling pathway of cross-interference between autophagy and different types of CVDs (28). Our research topic not only emphasizes the investigation of underlying mechanisms but also provides comprehensive reviews of cardiovascular damage resulting from drug toxicities. Liu et al. conducted a review that centered on targeted drug toxicity affecting the heart in the context of breast cancer (29), whereas Gona et al. delved into the subject of cardiovascular toxicity in relation to digoxin (30).
We listed these five key highlights in Table 1, and we are confident that the articles within our research topic offer fresh perspectives on metabolomic reprogramming associated with CVDs. This reprogramming presents therapeutic targets and drug toxicities for treating a variety of disease conditions, including as metabolic CVDs, diabetes, and breast cancer. It also enables conceptual innovation of trained immunity and disease progression.
Table 1. Five highlights of our research topic.
Author contributions
KX: Writing – original draft. FS: Writing – review & editing. YS: Writing – review & editing. YL: Writing – review & editing. XJ: Writing – review & editing. SW: Writing – review & editing. JS: Writing – review & editing. FS: Writing – review & editing. LM: Writing – review & editing. RV: Writing – review & editing. HW: Writing – review & editing. PY: Supervision, Writing – review & editing.
Conflict of interest
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.
Publisher's note
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References
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Keywords: metabolomics, cardiovascular diseases, cardiovascular injuries, inflammation, trained immunity
Citation: Xu K, Saaoud F, Shao Y, Lu Y, Jiang X, Wu S, Sun J, Fernades Conti F, Martinez L, Vazquez-Padron R, Wang H and Yang X (2023) Editorial: Debates in cardiovascular pharmacology and drug discovery: 2022. Front. Cardiovasc. Med. 10:1304680. doi: 10.3389/fcvm.2023.1304680
Received: 29 September 2023; Accepted: 9 October 2023;
Published: 18 October 2023.
Edited and Reviewed by: Masanori Aikawa, Harvard Medical School, United States
© 2023 Xu, Saaoud, Shao, Lu, Jiang, Wu, Sun, Fernades Conti, Martinez, Vazquez-Pedron, Wang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiaofeng Yang xfyang@temple.edu