Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Dalinac, N.
Mechanisms of trigger induced cardiac remodelling.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Bisping Egbert Hubertus
- Heinemann Akos
- von Lewinski Dirk
- Altmetrics:
- Abstract:
- Stretch and tachycardia are pathological events capable of triggering the heart to enter transcriptional and structural remodelling. Initially these events remain asymptomatic and are difficult to diagnose, until more severe changes occur. We aimed to better understand the molecular basis of how stretch and tachycardia induce the early events in cardiac remodelling. In this thesis, we performed two independent study parts by using (1) neonatal rat cell culture, suitable for dissecting pathological signalling events and cell specific actions, and (2) human multicellular trabeculae, which simulate a tissue specific response. By applying either stretch or tachycardia as a trigger in vitro we found an eccentric hypertrophy in the two prevalent cell types: myocytes and fibroblasts. Both triggers induced early remodelling genes in myocytes, but with different patterns. In non-myocytes only tachycardia had significant effects. Next we investigated the excitation transcription coupling (ETC) by inhibition of various ion handling proteins and characterized their effects on marker gene expression and whole genome wide microarrays. We could determine that: (a) stretch and tachycardia mediated effects mainly depend on the activation state of reverse mode of the sodium calcium exchanger (NCX), (b) inhibiting NCX prevented these effects as revealed by microarray analysis (40% of the effects in stretch and 18% in tachycardia), (c) stretch and tachycardia increased NCX activity, but stretch also increased NCX expression and (d) Calcium/Calmodulin-dependent protein kinase II (CaMKII) participated in the tachycardia mediated response downstream of NCX but not in the stretch response. In human atrial trabeculae (part 2) we applied acute stretch or tachycardia and observed largely independent gene regulations by using microarray technology. Only a small commonly regulated fraction was present. But within this we identified a miRNA precursor gene - MIR1183 as the most promising biomarker along with two of its putative downstream targets. MIR1183 was not only upregulated in acute stretch and tachycardia, but also in a chronic state of atrial fibrillation and in dilative cardiomyopathy. In conclusion, this thesis helps in taking a step forward in describing key features of early excitation transcription coupling, which are either stretch/tachycardia specific, or shared in their regulation including a promising biomarker for clinically relevant cardiac remodelling.