ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Zongwang Zhang is first author on ‘ A DUSP6 inhibitor suppresses inflammatory cardiac remodeling and improves heart function after myocardial infarction’, published in DMM. Zongwang is a PhD student in the lab of Jing-Wei Xiong at Peking University, Beijing, China, investigating therapeutic targets and drugs for cardiovascular diseases.
Zongwang Zhang
How would you explain the main findings of your paper to non-scientific family and friends?
Cardiovascular disease is the leading cause of death worldwide. Myocardial infarction is one of the cardiovascular diseases, considered as an epidemic in the modern world and a serious threat to human health and life. One of the main features of myocardial infarction is excessive inflammation followed by fibrotic scarring caused by excessive deposition of extracellular matrix during ventricular remodeling. However, there is no effective method to repair the heart by controlling inflammation in time and inhibiting the development of fibrosis. Previous studies in our laboratory found that inhibition of dual-specificity phosphatase (DUSP6) can promote heart regeneration in zebrafish and heart repair in rats. Therefore, we selected the DUSP6 small-molecule inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) to explore its effects on rats with myocardial infarction. The results showed that intravenous injection of BCI could improve cardiac function, and reduce myocardial apoptosis and cardiac fibrosis in rats with myocardial infarction, which was directly related to the inhibition of cardiac macrophages and neutrophil activity. BCI inhibited the differentiation of bone-marrow cells into macrophages. In addition, a single local injection of poly (D, L-lactate-glycolic acid)-coated BCI after myocardial infarction had a significant effect on cardiac repair. In conclusion, our work demonstrates that the DUSP6 inhibitor BCI is an attractive potential drug for the treatment of myocardial infarction, revealing a new mechanism by which BCI inhibits macrophage formation and inflammation.
“We demonstrate that BCI is an attractive potential drug for myocardial infarction, providing new mechanistic insights into the inflammatory response after myocardial infarction.”
What are the potential implications of these results for your field of research?
Compared with surgical treatment of myocardial infarction, drug therapy can reduce the pain of patients and avoid unnecessary injury. However, existing drugs for the treatment of myocardial infarction are limited, and the development of more effective small-molecule drugs has broad prospects. We report the beneficial effects of the DUSP6 inhibitor BCI by improving cardiac function and ameliorating cardiac inflammation and fibrosis, at least partly by weakening the p38–NF-κB signalling pathway. In conclusion, we demonstrate that BCI is an attractive potential drug for myocardial infarction, providing new mechanistic insights into the inflammatory response after myocardial infarction. Thus, BCI can be used for the treatment of heart disease and other related inflammatory diseases.
What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?
We selected rats as the subjects for myocardial infarction operation, which was more convenient for experimental operation and better parallelism of results compared with choosing mice. Intravenous and intracardiac injections allow drugs to reach the area of heart damage faster and more efficiently. However, this study also has some limitations. For example, the long-term efficacy of BCI in rats with myocardial infarction requires further exploration. After a single local injection, the heart function does not continue to recover, which may be due to the drug mostly having been metabolized or utilized the first time. BCI is characterized by poor solubility, and structural modification is still needed to improve the solubility of the drug in our future studies.
H&E staining of rat heart following treatment with BCI after myocardial infarction. Compared with the vehicle group, the BCI group showed decreased collagen deposition and immune cell infiltration. Scale bar: 300 µm.
What has surprised you the most while conducting your research?
BCI was previously reported to be a DUSP6 inhibitor, but we were surprised to find that deletion of Dusp6 did not reduce lipopolysaccharide-induced inflammation, and BCI still had anti-inflammatory effects in Dusp6 mutants, indicating that inhibition of inflammation by BCI was not dependent on DUSP6, but depends on NF-κB pathway inhibition. This suggests that BCI has a unique inhibitory effect on inflammation beyond the role of DUSP6 inhibitor.
What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
How to translate current preclinical results into the clinic to help patients with cardiovascular disease is the most significant challenge. Next, we will start with the screening of DUSP6 inhibitors, search for new inhibitors that can inhibit DUSP6 protein, and preliminarily explore their efficacy and molecular mechanisms in animal models. Based on this research idea, new DUSP6 inhibitors that are more efficient and have clinical translational significance will be selected.
What changes do you think could improve the professional lives of scientists?
I think online as well as offline communication will be important. The main purpose of the exchange is to communicate, so that participants can exchange experience, knowledge and research progress with each other. But why communicate at all? In most cases, what one can pay attention to is limited. Even if one is immersed in the same field of research for a long time, there may be some neglected information, which may sometimes play a decisive role, especially in the scientific community.
What's next for you?
Next, I will finish my doctoral dissertation. My main research direction is the discovery of therapeutic targets and drugs for cardiovascular diseases. I hope to find new targets and drugs to improve these diseases in the following research.
Zongwang Zhang’s contact details: Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
E-mail: [email protected]
