https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2Universitätsmedizin Göttingen Herzzentrum Göttingen - Stem Cell Unit Göttingen, Deutschland; 3Medizinische Fakultät Mannheim FlowCore Mannheim Mannheim, Deutschland; 4Medizinische Fakultät Mannheim Cardiovascular Genomics and Epigenomics Mannheim, Deutschland
Aims
Acute myocardial infarction (MI) induces pathways of inflammation, apoptosis and fibrosis in the myocardium affected by coronary artery occlusion (ischemia) and re-opening (reperfusion), resulting in scar formation and, ultimately, in derangements of contractile and electric properties. Similar changes are observed in the remote myocardium, although not targeted by the ischemia-reperfusion event, leading similarly to changes in tissue characteristics after MI. We developed a cell culture model of remote myocardium to study the cause of the biomolecular changes induced by an MI.
Methods
Healthy hiPSC-derived cardiomyocytes were incubated with plasma collected from patients during acute MI. Expression of genes and proteins of apoptosis and fibrosis were studied by PCR and Western blotting. FACS analysis were performed to assess induction of apoptosis. Mitochondrial metabolism and function were studied by JC-10 assay, ATP and ROS measurements.
Results
MI plasma induced the activation of caspase-3 both qualitatively and quantitatively, but reduced the expression of FOXO3 and HIF1alpha. The secretion of the FOXO3 stabilizing protein osteopontin was reduced by MI plasma as well. While mitochondrial membrane potential or cellular metabolic activity were not affected, incubation with MI plasma greatly decreased ATP production while increasing ROS levels. Consequently, the fraction of viable cells was reduced, while the fraction of apoptotic cells was increased by MI plasma.
Conclusion
Plasma from patients with MI induces changes in healthy hiPSC-cardiomyocytes observed otherwise in myocardium targeted directly by an ischemia-reperfusion injury due to coronary occlusion and re-opening. These observations indicate involvement of pathways of apoptosis and fibrosis due to mitochondrial dysfunction in the remote myocardium after MI, solely induced by exposure to patient’s plasma. While re-opening the target vessel might reduce the injury of the MI area, approaches of preventing damage of the remote myocardium during MI have to be defined yet.