On 27 September at 14:15 Kattri-Liis Eskla will defend her doctral thesis „Therapeutic strategies forischemia reperfusion injury“.
Supervisors:
Senior Research Fellow in Human Physiology, Hendrik Luuk
Christian Ansgar Hundahl (PhD, Novo Nordisk, Denmark)
Professor of Human Physiology Eero Vasar
Oponent:
Daniel A. Tennant (PhD, Reader in Metabolic Biochemistry, University of Birmingham,Birmingham, UK).
Summary:
Ischemic-hypoxic injury is caused by diminished or absent blood flow and result of oxygen deprivation (e.gstroke, heart attack). It encompasses a complex constellation of pathophysiological and molecular injuries, ifleft untreated can result in death. In this dissertation we studied therapeutic mechanisms that might beprotective against ischemia reperfusion injury in order to enhance both our knowledge of ischemia reperfusioninjury pathophysiology and mechanisms of protection. Clinical hypothermia is considered as one of the mosteffective intervention for a range of hypoxic ischemic pathologies of the central nervous system, however, themechanisms that underlie its protective effects are uncertain. Currently, it is widely accepted that therapeuticeffects of hypothermia are due to reduced metabolism and oxygen consumption. Our study demonstrates forthe first time that mild hypothermia activates major transcription factors Nrf2 and HIF1A, which orchestrateadaptive responses to hypoxic stress.
Hydrogen sulfide (H2S) is now recognized as a novel gaseous signaling molecule along with nitric oxide and carbon monoxide, although it was considered to be a toxic gas for hundreds of years.We show here that notonly does H2Sregulate mitochondrial biogenesis via AMPK-PGC1α signaling pathway but also that correctingH2S levels with SG-1002 (H2S-releasing prodrug) could protect against heart failure. The lymphatic systemhas been suggested to play an important role in cardiovascular disease. Our results show that inhibition ofcardiac lymphangiogenesis exaggerates ischemia reperfusion injury even more. Furthermore,stimulation ofcardiac lymphangiogenesis with VEGF-C improves cardiac function following ischemia reperfusion injury. This dissertation provides clues to additional opportunities that could be translated into more efficienttherapeutic approaches towards ischemia reperfusion injury.