The role of HMGB1 in myocardial infarction

Thesis

Coronary artery disease remains the leading cause of morbidity and mortality worldwide, and approximately 100,000 people in the UK suffer myocardial infarction (MI) every year. The mainstay of treatment for MI remains reperfusion. However, despite the therapeutic advances, approximately one-third of patients go on to develop heart failure. Animal models of MI have their limitations and in vitro models based on human cardiomyocytes provide additional valuable mechanistic insights. In this thesis, I describe how I developed a method to generate mature cardiomyocytes from human embryonic stem cells by culturing them in glucose-depleted and fatty acid-enriched media together with electrical stimulation. Next, I optimised an in vitro model of repeated cycles of hypoxia followed by normoxia to emulate ischaemia reperfusion injury and investigated the effects of fully reduced HMGB1 (FRHMGB1) using this system. I found that HMGB1 reduced injury and improved cell survival by upregulating mitochondrial pathways in a mammalian target of rapamycin complex (mTORC) and peroxisome proliferator-activated receptor g coactivator-1a-dependent manner. I also found that FR-HMGB1 reversed doxorubicin-induced cardiotoxicity, again through upregulation of mitochondrial pathways. Finally, I investigated the efficacy of a nonoxidisable HMGB1 construct (double Box B – dBB) and found that it was more effective than FR-HMGB1 in ameliorating the effects repeated cycles of hypoxia and doxorubicin. Taken together, my results show that HMGB1 constructs could be used to treat ischaemia reperfusion injury following MI and doxorubicin-induced cardiotoxicity.

Authors: Lee, C

• DOI: 10.5287/ora-dedzwd5kk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: hESC-CM; HMGB1; cardiology; stem cells
• Subjects: Cardiology; Embryonic stem cells; Myocardial infarction; Medicine