Circadian Cardioprotection: BMAL1/HIF2A Complex and Co-target Amphiregulin

Since she ventured into the anesthesiology specialty, Wei Ruan, PhD, MD, has possessed mighty optimism for what might be accomplished to improve patient care through anesthesia research and has set out to play an integral part in this advancement. An Assistant Professor in Anesthesiology at The University of Texas Health Center at Houston, Dr. Ruan hopes to change the landscape of perioperative cardioprotection, searching for novel interventions to improve myocardial resistance to ischemia. This shift in landscape could prove monumentally important for surgical patients who are at high risk for comorbidities and complex procedures. Recently, her ambitious efforts were recognized with a 2022 IARS Mentored Research Award for her current research study, Circadian Cardioprotection: BMAL1/HIF2A Complex and Co-target Amphiregulin. In her investigations, she is exploring the specific mechanisms behind the cardioprotective effects of the BMAL1/HIF2A heterodimer through transcriptional induction of the target gene AREG. She hopes to unearth critical knowledge about the role of circadian rhythm in perioperative cardioprotection, potentially identifying new therapeutic targets for perioperative myocardial IRI to improve outcomes for surgical patients. Below, she shares her research journey, how this award will positively impact her research and future as a physician-scientist and her vision for the future of anesthesia research.

1. What drew you to this area of research?

My interest in perioperative cardioprotection stemmed from a desire to gain insights into the factors contributing to cardiovascular outcomes in individuals undergoing cardiac surgical procedures. My research journey started during my PhD studies at Xiangya Medical School in Central South University in China, where I investigated the therapeutic potential of miRNA-23a in reducing myocardial injury. As a cardiac anesthesiologist, I furthered my research on sepsis-induced cardiac dysfunction in a perioperative medicine lab and discovered the cardioprotective effects of PPAR-γ and BDNF.

With additional funding from the National Natural Science Foundation of China and the Natural Science Foundation of Hunan Province, I focused on the cardioprotective effects of microparticles derived from myocardial ischemia-reperfusion injury (IRI), utilizing genomics, bioinformatics, and coding in R to analyze complex gene-environment interactions.

As a visiting scientist and postdoctoral fellow in the USA, I worked in Dr. Holger Eltzschig’s lab, where I gained expertise in hypoxia-related pathways in myocardial ischemia-reperfusion injury. My research progress in studying the role of hypoxia signaling during myocardial injury in the context of hypoxia-inducible factors (HIFs) and adenosine signaling pathways inspired me further to investigate the functional role of circadian rhythm and hypoxia pathways in cardiovascular diseases.

2. What is the goal of your research?

The goal of this research is to investigate the role of circadian rhythm in perioperative cardioprotection. The study aims to explore the specific mechanisms behind the cardioprotective effects of the BMAL1/HIF2A heterodimer through transcriptional induction of the target gene AREG. We will use genetic and transcriptional studies to dissect the role of the BMAL1/HIF2A heterodimer in vitro. Additionally, the study will investigate the circadian-dependent cardioprotection of the BMAL1/HIF2A-AREG pathway during ischemia-reperfusion injury (IRI) in vivo. Through transgenic mice and pharmacologic studies, we aim to demonstrate the functional role of AREG in the daytime variation of myocardial IRI and identify a circadian-based treatment for myocardial IRI.

3. What is the potential impact of your research on the field of anesthesia?

The potential impact of this research on the field of anesthesia is significant. Perioperative myocardial ischemia-reperfusion injury (IRI) is a major cause of morbidity and mortality in surgical patients, particularly those who are high-risk due to comorbidities and complex procedures. Finding novel interventions to improve myocardial resistance to ischemia is critical, and targeting circadian rhythm for perioperative cardioprotection could be a promising strategy. Understanding the mechanisms providing circadian cardioprotection could be exploited directly for perioperative cardioprotection, utilizing circadian enhancers like nobiletin or HIF activators. Additionally, clock-based interventions could be tested to enhance cardioprotection at specific vulnerable periods of the day. Overall, this research has the potential to identify new therapeutic targets for perioperative myocardial IRI and improve outcomes for surgical patients.

4. How do you feel about receiving the IARS Mentored Research Award?

I am honored and humbled to have been selected as the recipient of the prestigious IARS Mentored Research Award. This highly competitive research grant provides significant support and resources to early-career researchers, and being chosen for such a distinction is an incredible privilege. I am grateful for this opportunity to pursue my research interests and contribute to the field of anesthesia research.

Receiving this award is not only a recognition of my potential but also a testament to the hard work and dedication of my mentors, colleagues, and collaborators who have supported me along the way. I am excited to take on the responsibility that comes with this award and commit to conducting rigorous and impactful research that can lead to improved patient care and outcomes.

I am eager to collaborate with experts in the field, explore new ideas, and leverage the resources and support provided by this award to advance our understanding of perioperative myocardial ischemia-reperfusion injury and the role of circadian rhythm in cardiac protection. I believe that this research has the potential to make a significant impact on patient care and outcomes, and I am honored to have the opportunity to contribute to the field of anesthesia research in this way.

5. How will this award affect your research/professional trajectory?

Receiving the IARS Mentored Research Award will have a significant impact on both my research and professional trajectory. The award’s financial and institutional support will enable me to pursue my research interests more extensively, which will lead to significant contributions to the field of anesthesia research. The mentorship and networking opportunities offered by the award will also provide me with invaluable guidance and connections as I continue to advance in my career.

Additionally, the recognition and prestige that come with the award will help me secure future funding and career opportunities, further advancing my research and professional trajectory. Overall, receiving the IARS Mentored Research Award will be pivotal in my professional journey, providing me with the resources, recognition, and opportunities necessary to contribute significantly to my field.

As a result of the award, I will be able to work towards my long-term career goal of becoming an NIH R01-funded independent investigator in the field of perioperative myocardial ischemia-reperfusion injury (IRI). To achieve this goal, I plan to lay the groundwork of basic research to develop novel therapeutic targets for treating or preventing myocardial IRI and improving outcomes in critically ill patients. As a cardiovascular anesthesiologist, I also intend to strengthen the collaboration between basic research and clinical studies to identify novel therapeutic targets.

Furthermore, the award will help me establish a laboratory in the next five years, providing excellent training for graduate students and postdoctoral candidates and cultivating young physicians’ interests in basic science to become clinician-scientists. The IARS Mentored Research Award will undoubtedly facilitate my career path toward becoming an independent investigator and making significant contributions to the field of anesthesia research.

6. Is there anyone else you wish to acknowledge as part of this research team?

Thank you for the opportunity to acknowledge the individuals who have contributed to this research. I would like to extend my gratitude to my three mentors, Drs. Holger Eltzschig, Changqing Ju and Kuang-Lei Tsai who provided invaluable guidance and support throughout this project. Their expertise and mentorship have been instrumental in shaping my research direction and approach.

7. Outside of your research, what might someone be surprised to learn about you?

One thing that might come as a surprise to some people is that I enjoy drawing and painting in my free time. I have always enjoyed creating art ever since I was a child. As I grew older and became more involved in scientific research, I found that I needed a way to unwind and destress from the technical and analytical aspects of my work. That’s when I rediscovered my love for art and began to incorporate it into my leisure time.

I have found that the act of creating art helps me to clear my mind and focus on something other than my research. Whether it’s working on a detailed pencil sketch or experimenting with different paint colors and textures, the creative process is both challenging and rewarding.

Additionally, I enjoy exploring different art forms and techniques, such as watercolor painting, charcoal sketching and mixed media collage. I have even taken some classes and workshops to improve my skills and learn new techniques.

Overall, my passion for art provides me with a much-needed break from the rigors of scientific research and allows me to express myself in a different way. I am always surprised by the positive impact that creating art has on my mental well-being and stress levels, and I believe it’s important for everyone to find a creative outlet that helps them to recharge and refocus.

8. What is your vision for the future of anesthesia research?

The future of anesthesia research should prioritize patient safety and outcomes while fostering a collaborative environment for basic and translational research. Since anesthesia plays a crucial role in many medical procedures, it is vital to continue improving our understanding of the mechanisms underlying anesthesia and pain management and the potential complications associated with these interventions.

To enhance patient safety and outcomes, future anesthesia research should focus on identifying new approaches for patient monitoring, individualizing anesthetic management, and reducing the incidence of adverse events like postoperative delirium, cognitive dysfunction and chronic pain. This can be achieved through the development of new pharmacological agents, advancements in monitoring technology and innovative approaches to perioperative care.

Translational research is also necessary for the future of anesthesia research. It helps translate basic science discoveries into clinical applications, identify novel therapeutic targets for anesthesia-related complications, develop new drugs and devices and improve patient outcomes. For this, it is essential to create a collaborative environment between basic scientists, clinicians, and industry partners.

Clinical trials are also essential for evaluating the safety and efficacy of new interventions and therapies. To improve patient outcomes, future clinical trials should focus on testing interventions tailored to individual patient needs and identifying biomarkers that can help predict and prevent anesthesia-related complications. Additionally, incorporating real-time data monitoring into adaptive and innovative trial designs may help identify effective interventions more efficiently while minimizing patient risk.