Medizinische Universität Graz - Research portal
Selected Publication:
Voglhuber, J.
The (peri)nuclear region in cardiac remodelling
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp.
- Authors Med Uni Graz:
- Advisor:
- Holzer Senka
- Madl Tobias
- Sedej Simon
- Altmetrics:
- Abstract:
- Cardiac remodelling refers to the process of structural and functional alterations occurring during the development and progression of cardiovascular disease. Initially, patients remain asymptomatic, making diagnosis challenging. However, as the disease advances, they transition into more severe stages of cardiac dysfunction and ultimately heart failure (HF). A growing body of evidence suggests that the (peri)nuclear region plays a causal role in initiation and progression of cardiac remodelling. Consequently, this thesis places a strong emphasis on investigating this subcellular microdomain to uncover new therapeutic targets. In the first part, the focus was investigating the dysfunction of the perinuclear (PN) mitochondrial subpopulation in the early and late phases of HF compared to intrafibrillar (IF) mitochondria. Here, it was demonstrated that PN mitochondria in cardiomyocytes from mice with HF undergo earlier and more severe functional changes compared to IF mitochondria. Further, it was found that PN mitochondrial Ca2+ uptake is essential for physiological nucleoplasmic Ca2+ transients. Normalising PN mitochondrial Ca2+ uptake could potentially ameliorate aberrant nuclear Ca2+ signalling, an early driver of cardiac remodelling. The second part revolved around (peri)nuclear changes affecting excitation-transcription coupling. In cardiomyocytes from hypertensive rats the subcellular activation profile of Ca2+/calmodulin-dependent protein kinase II (CaMKII) is aberrant, with enhanced activity at the cellular Ca2+ stores during early stages indicating an adaptive phase, and CaMKII overactivation in the nucleoplasm of the late stage, indicating a maladaptive phase. Further the expression and localisation of the inhibitory regulator of CaMKII, protein arginine methyltransferase 1 (PRMT1) were negatively affected. Additionally, hypertensive cardiomyocytes exhibited blunted β-adrenergic signalling. Collectively, this has effects on the transcriptome and arginine methylation profile, highlighting the relevance of the CaMKII-PRMT1 signalling axis in the progression of cardiac remodelling. Ultimately, in the third part, β-adrenergic stress and tachycardia as potent triggers of cardiac remodelling were investigated in an in vitro model. Tachycardia resulted in the upregulation of the Na+/Ca2+ exchanger (NCX) and increased pCaMKII levels in the (peri)nuclear region. This led to a pro-hypertrophic and pro-inflammatory transcriptional response. β-adrenergic stimulation mitigated these transcriptional alterations by downregulating NCX and potentiating CaMKII activity at cellular Ca2+ stores. Finally, blunted β-adrenergic signalling could be confirmed to be associated with NCX upregulation in hypertensive rats. This underscores the importance of intact β-adrenergic signalling, which is compromised in cardiac pathologies.