Rolle der Phosphodiesterase 2 in der menschlichen und experimentellen Herzinsuffizienz
Phosphodiesterase 2A regulation in human and experimental heart failure
Julius Emons
Doctoral thesis
Date of Examination:
2017-10-17
Date of issue:
2017-09-14
Advisor:
El-Armouche, Ali Prof. Dr.
Referee:
El-Armouche, Ali Prof. Dr.
Referee:
Kaul, Axel Dr.
Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0023-3F03-1
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Abstract
English
Background: Cyclic nucleotide phosphodiesterases (PDEs) compromise a family of cyclic-nucleotide hydrolysing enzymes, controlling the levels of cAMP and cGMP in a highly specific and stimulus-dependent manner. Amongst them, the PDE2A isoform is a dual specificity enzyme, hydrolyzing cAMP and cGMP. PDE2A is unique in being allosterically activated by cGMP, resulting in enhanced cAMP hydrolysis. This characteristic of PDE2A allows a negative cross-talk between both signaling pathways. Here, we hypothesized that alterations in PDE2A may contribute to the well-known imbalance between cAMP- and cGMP- signaling pathways in failing hearts. Methods and results: PDE2A protein levels were determined in left ventricular myocardium from patients with terminal heart failure (hHF; n=10) compared to non-failing donor-hearts (NF; n=6) and from dogs subjected to rapid-pacing induced heart failure (dHF; n=9) compared to Sham-operated controls (Sham; n=9) by western blotting using PDE2A-specific antibodies. PDE2A protein levels were ~ 4-fold higher in the human failing hearts compared to NF (3.8±0.5 -fold, p<0.05) and ~ 2-fold higher in failing dog hearts compared to Sham (dHF: 1.9±0.3, p<0.05), indicating a potentially important pathological role for PDE2A in heart failure. Furthermore, rats treated chronically with the -adrenoceptor agonist isoprenaline showed ~2-fold higher PDE2A protein amount compared to NaCl-treated control rats (Iso: 1.8±0.3, n=8, p<0.05), suggesting that excessive adrenergic drive, which occurs in heart failure, contributes partially to PDE2A upregulation. To gain further insight with respect to the overall role of PDE2A in the heart, e.g. intracardial cellular distribution, we compared the PDE2A abundance in cardiac fibroblasts and cardiac myocytes from neonatal mouse hearts. Interestingly, PDE2A abundance was 4-fold higher in fibroblasts compared to cardiomyocytes (n=7, p<0.05), indicating a potentially important role for PDE2A in the regulation of fibroblast activity. Finally, immunofluorescence analysis in adult cardiomyocytes revealed that the PDE2A protein is confined to the membrane compartment within the sarcomeric Z line, indicating preferential subsarcolemmal cAMP/cGMP level regulation. Conclusion: PDE2A protein levels are markedly increased in human and experimental heart failure. This may either contribute to or compensate for the imbalance between cAMP and cGMP signaling pathways in failing hearts. Extensive subsequent work, including the generation of a transgenic mouse model, has been started to improve the understanding of the physiological and pathological consequences of altered PDE2A abundance in the heart.
Keywords: PDE2; Phosphodiesterase 2; heart failure
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Human- und Zahnmedizin [2120]