Therapy and mechanisms of cardiac ischemia-reperfusion injury

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.