Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rech, C.
Inflammatory responses in myocardial infarction remodeling
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 73
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Birner-Grünberger Ruth
- Rainer Peter
- von Lewinski Dirk
- Altmetrics:
- Abstract:
- Cardiovascular diseases (CVDs) are one of the tremendous burdens of today. Within these, a major group encompass ischemic heart diseases, including myocardial infarction (MI). Occlusion of coronary vessels leads to hypoxia in the myocardium and causes the death of cardiomyocytes. Clean-up of cell debris and wound healing needs inflammatory processes. These processes are precisely balanced between a pro-inflammatory and a pro-reparatory phase. Extensive inflammation, however, promotes infarct expansion and adverse remodeling. Involved in recognising the need for an inflammatory response is the cGAS-STING pathway. It is part of the first-line immune defence of the innate immune system. The enzyme cGAS senses DNA, which is not located in the nucleus or the mitochondria, and activates downstream STING, leading to the transcription of type I interferon (IFN). Recent papers demonstrated that this pathway is also active following MI and that its genetic targeting though inactivation leads to improved ventricular function. Thus, we investigated if pharmacologic pathway inhibition is protective after MI. Therefore, we operated C57/BL6J male mice to induce MI and used sham-operated mice as controls. Further, we injected these mice daily i.p. with a STING-inhibitor or vehicle control. We used echocardiography, histology, and qPCR to assess changes in myocardial remodeling based on STING inhibition. In a permanent ligation model, STING inhibition did not reduce mortality due to myocardial rupture. Further, the IFN-induced genes (Ifi44, Ifit2, Cxcl10, Isg15) did not show significant differences after four days. In ischemic/reperfusion (I/R) model infarct size was comparable at day 1. After three weeks of daily treatment, we observed decreased infarct expansion and scarring, increased left ventricular systolic function to levels approaching normal values, and reduced myocardial hypertrophy. Additionally, a significant decrease in molecular levels in the infarct zone could be observed in the IFN-induced genes Ifi44 and Cxcl10 and further a decreasing trend in Ifit2 and Isg15. In conclusion, selective small-molecule STING inhibition after myocardial infarction has the potential to improve wound healing responses and pathological remodeling and thereby attenuate the negative development of ischemic heart failure.