Our overall goal is to save tissue during early reperfusion by targeting the innate immune system. By reducing detrimental effects of damage associated molecular patterns (DAMPs) we aim to save tissue and reduce development of heart failure. We hypothesize that mitochondria are particular immunogenic due to their bacterial origin. Our main models are primary mice cardiomyocytes, ex vivo perfused isolated hearts and in vivo myocardial ischemia reperfusion. We are investigating cardiomyocyte viability after exposure to mitochondrial DAMPs (mDAMPs). In the isolated perfused heart we utilize blockers of innate immune receptors and others, and investigate infarct size after reperfusion. Similar experiments are performed in the in vivo system were heart function are analyzed with ultrasound (Vevo3100).
The way cardiomyocytes die have dramatic consequences for the remaining healthy tissue. Sensed from the immune system, apoptosis has less release of DAMPs, while with necrosis, “everything” is released. Necrosis have until recently been considered an accidental cell death. However, the discovery of regulated necrosis, or necroptosis, radically changed the view on cell death and has opened up new treatment options for human diseases. Necroptosis also includes loss of membrane integrity and release of cellular DAMPs, but are dependent on the receptor-interacting protein kinase 1 (RIPK1)-RIPK3 complex.
We have established a system with the immortal cardiac cell line HL-1 with hypoxia and reoxygenation to simulate ischemia-reperfusion injury. In the HL-1 cells we can study molecular mechanisms of necroptosis. We also perform ex vivo heart perfusion using necrostatins to block necroptosis.
Refinement of methods used for functional cardiac evaluation
Many of the methods used in cardiovascular research have been around for a very long time and have been thoroughly tested. Still, some of the methods have unwanted consequences and we work continuously to understand the mechanisms behind these. We are particularly interested in the isolated heart system and perfusion according to Langendorff.
Anoxia tolerant mitochondria
Mammals are very sensitive to reduced oxygen (hypoxia), while some other vertebrates can survive extreme long exposure to no oxygen (anoxia). The freshwater fish, crucian carp can survive several months without oxygen at cold temperature. We are particularly interested in how mitochondria can maintain integrity without oxygen.
Aortic valve calcification
Calcific aortic valve disease (CAVD) is a slow progressive disorder ranging from non-symptomatic thickening of valve leaflets (aortic valve sclerosis) to severe calcification with aortic valve stenosis. It is the most common form of valve disease in the western world and with ageing populations, will become an increasing health burden.
We are using human valve cells which are cultivated in vitro. We study myofibroblastic and osteoblastic differentiation. We are testing potential inhibitors of calcification in this in vitro system.