• Yilan Shen

Student thesis: Master of Philosophy


Normal cardiac physiology largely relies on calcium handling in cardiomyocytes by a process called excitation-contraction coupling (ECC), in which the calcium pump, the sarco(endo)plasmic reticulum calcium ATPase (SERCA) and its predominant inhibitor, phospholamban (PLN), play important roles. Dysfunction in ECC can cause heart failure which is a leading cause of death worldwide with a five-year death rate of ~50%. It was reported in many early studies in heart failure that SERCA abundance and function is downregulated whilst PLN abundance remained unchanged. However, the levels of phosphorylated PLN (pPLN) are often noted to be downregulated and contributing to the reductions in SERCA activity. Gene therapy of SERCA has been demonstrated to be an effective therapeutic target in animal models of HF. However, this approach failed to make progress in multiple clinical trials. This study used a myocardial infarction ovine model that is comparable to human ischaemia reperfusion induced heart failure to determine SERCA, PLN and pPLN abundance in the remote and border regions of the infarcted left ventricle, and to investigate the hitherto overlooked area - the sub-cellular distribution of SERCA and PLN with high-resolution nanoscale STORM imaging. This study found that SERCA protein abundance has significantly increased in the remote region 20 weeks MI compared to control There was no change in PLN abundance, and a decrease in pPLN levels compared to control. These findings emphasize the importance of pPLN in heart failure pathogenesis which might explain why SERCA gene therapy was not effective. There was no change in either SERCA cluster size or distance after phosphorylation. However, this study also found PLN has a smaller distance between clusters after phosphorylation which is possibly due to PLN pentamerization. It would be intriguing to see whether this PLN redistribution is altered in heart failure in the future study, and if redistribution is observed, this might give a new therapeutic target in treating heart failure.
Date of Award31 Dec 2022
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorAndy Trafford (Supervisor) & Katharine Dibb (Supervisor)


  • PLN
  • heart failure

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