Potential role of Proenkephalin (PENK) in right heart failure

Jannis Völker (Gießen)1, B. Niemann (Gießen)2, L. Li, (Gießen)1, L. Czech (Gießen)1, K.-D. Schlüter (Gießen)1, M. Kracht (Gießen)3, S. Rohrbach (Gießen)1

1Justus-Liebig-Universität Giessen Physiologisches Institut Gießen, Deutschland; 2Universitätsklinikum Gießen und Marburg GmbH Klinik für Herz-, Kinderherz- und Gefäßchirurgie Gießen, Deutschland; 3Rudolf-Buchheim-Institut für Pharmakologie Gießen, Deutschland



Despite many similarities between the left ventricle (LV) and the right ventricle (RV), important differences in development, anatomy, pathophysiology, and clinical management exist. However, the molecular mechanisms of progressive RV failure are incompletely understood. By performing a systematic comparison of RV and LV cardiomyocytes from rats with slowly progressing RV failure (RVF) or LV failure (LVF), we identified gene signatures, proteins, and transcription factor (TF) networks specific for each ventricle, disease state, and the type of heart failure. Among the proteins implemented in RVF progression in those rats but also in patients with chronic thromboembolic pulmonary hypertension (CTEPH), was proenkephalin (PENK). The opioid-receptor-system is well known in central nervous system and therapeutic interventions in the system are widespread. However, endogenous opioids take an important role in the (patho)physiology of various other organs including the cardiac system. In mammalian hearts, all types of opioid receptors and their ligands are expressed, but enkephalins appear to take a leading role in this system. Proenkephalin (PENK) as the precursor of enkephalins seems to be a negative prognostic marker in heart failure as it correlates with severity, mortality and rehospitalization rate of heart failing patients.



To identify RV-specific signatures, we established rat models, which show two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Gene expression was analyzed by RNA-sequencing, proteomics analyses, qPCR and Western blot. Focusing on one of the target genes (PENK) identified by RNA sequencing and proteomic analyses from these rats, we tested conditions of PENK induction and analyzed the functional impact of PENK in adult rat cardiomyocytes.



PENK is upregulated in the PAB-/AOB model both in RV and LV tissue and in cardiomyocytes in comparison to sham animals at both disease stages (RNA seq. data, proteomics, qPCR, Western blot). Interestingly, the intersection of rat PAB-specific gene sets with 95 transcriptome data sets from CTEPH patients led to the identification of more than 50 genes, among those Penk, whose expression levels strongly correlate with the severity of RV disease. Within the heart, cardiomyocytes show a strong Penk expression. A screening with typical mediators involved in heart failure-associated neurohumoral activation (angiotensin II, TNF-alpha, catecholamines, endothelin-1 etc.), showed a strong induction of PENK expression in cardiomyocytes in response norepinephrine or endothelin-1 stimulation. Furthermore, the contractile response of isolated rat cardiomyocytes was significantly impaired following short-term incubation with enkephalin (Leu-Enkephalin, 100nM). Interestingly, this appears to be more pronounced in LV cardiomyocytes than in RV cardiomyocytes. In addition to these effects on cardiomyocyte contractile function, proenkephalin is able to attenuate the pro-hypertrophic effects of the alpha1 adrenergic agonist phenylephrine. Here, a comparable effect of proenkephalin was observed in RV and LV cardiomyocytes.



Proenkephalin (Penk) was among the top regulated genes/proteins in rat RV failure. It mediates manifold functional effects on isolated cardiomyocytes and its expression is induced during heart failure-associated neurohumoral activation.

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