- Author
-
Y. Xiao
- Title
- Therapy and mechanisms of cardiac ischemia-reperfusion injury
- Supervisors
- Co-supervisors
-
C.J. Zuurbier
N.C. Hauck-Weber - Award date
- 21 December 2022
- Number of pages
- 209
- ISBN
- 9789464587494
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Acute myocardial infarction (AMI or heart attack), in which myocardial damage is primarily the result of ischemia-reperfusion (I/R) injury, remains the leading cause of morbidity and mortality worldwide. This thesis aims to explore therapeutic strategies for acute myocardial I/R injury and reveal the mechanisms underlying I/R injury. We first evaluated several promising cardioprotective compounds in an in vivo model employing clinically relevant anesthesia, showing that only nicotinamide riboside (NR; NAD precursor) reduced I/R injury in presence of clinic therapies. We then showed in the isolated heart that NR’s protection is through activation of glycolysis. Next, knowing that oxidative stress is a major initial triggers for I/R injury, a recently developed clinically-applicable antioxidant compound (KH176m) was examined and shown higher efficacy of cardioprotection than the classic antioxidant N-(2-mercaptopropionyl)-glycine. However, antioxidant protection was mostly shown for short, but not long, ischemia. Additionally, we examined the NOD-like receptors X1 (NLRX1), an anti-inflammatory mitochondrial innate immune receptor which was shown to protect against severe ischemia. By deep-diving into the mechanisms, NLRX1 was proven to be a novel constituent of the mitochondrial permeability transition pore (mPTP), regulate mitochondrial function, and indirectly contribute to cardioprotection by facilitating reperfusion injury salvage kinase (RISK) pathway activation. After 70 years of searching for the molecular identity of the mPTP, NLRX1 is a strong candidate to finally fill that knowledge gap. In conclusion, this thesis addresses several strategies for acute cardiac I/R injury and unravelling the underlying protecting mechanisms improves our understanding of the crucial pathological processes of I/R injury.
- Persistent Identifier
- https://hdl.handle.net/11245.1/d77a7aca-6f48-4802-bf9c-0546e9d80abe
- Downloads
-
Thesis (complete)
Chapter 1: General introduction
Chapter 2: Efficacy of cardioprotective interventions depends critically on duration of ischemia
Chapter 3: Cardioprotective properties of known agents in rat ischemia reperfusion model under clinically relevant conditions: Only the NAD precursor nicotinamide riboside reduces infarct size in presence of fentanyl, midazolam and cangrelor, but not propofol
Chapter 4: Glycolytic dependence of cardioprotection by nicotinamide riboside
Chapter 5: The redox modulating sonlicromanol active metabolite KH176m and the antioxidant MPG protect against short-duration cardiac ischemia-reperfusion injury
Chapter 6: NLRX1 deletion increases ischemia-reperfusion damage and activates glucose metabolism in mouse heart
Chapter 7: The innate immune receptor NLRX1 in cardiac ischemia-reperfusion injury: A novel regulator of mitochondrial pore opening
Chapter 8: Summary
Chapter 9: General discussion
PhD portfolio; Acknowledgements
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library, or send a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.