- Title
- β-Adrenergic Receptor Stimulation Maintains NCX-CaMKII Axis and Prevents Overactivation of IL6R-Signaling in Cardiomyocytes upon Increased Workload
- Creator
- Matzer, Ingrid; Voglhuber, Julia; Zirlik, Andreas; Ljubojevic-Holzer, Senka; Kiessling, Mara; Djalinac, Nataša; Trummer-Herbst, Viktoria; Mabotuwana, Nishani; Rech, Lavinia; Holzer, Michael; Sossalla, Samuel; Rainer, Peter P.
- Relation
- Biomedicines Vol. 10, Issue 7, no. 1648
- Publisher Link
- http://dx.doi.org/10.3390/biomedicines10071648
- Publisher
- MDPI
- Resource Type
- journal article
- Date
- 2022
- Description
- Excessive β-adrenergic stimulation and tachycardia are potent triggers of cardiac remodeling; however, their exact cellular effects remain elusive. Here, we sought to determine the potency of β-adrenergic stimulation and tachycardia to modulate gene expression profiles of cardiomyocytes. Using neonatal rat ventricular cardiomyocytes, we showed that tachycardia caused a significant upregulation of sodium–calcium exchanger (NCX) and the activation of calcium/calmodulin-dependent kinase II (CaMKII) in the nuclear region. Acute isoprenaline treatment ameliorated NCX-upregulation and potentiated CaMKII activity, specifically on the sarcoplasmic reticulum and the nuclear envelope, while preincubation with the β-blocker propranolol abolished both isoprenaline-mediated effects. On a transcriptional level, screening for hypertrophy-related genes revealed tachycardia-induced upregulation of interleukin-6 receptor (IL6R). While isoprenaline prevented this effect, pharmacological intervention with propranolol or NCX inhibitor ORM-10962 demonstrated that simultaneous CaMKII activation on the subcellular Ca2+ stores and prevention of NCX upregulation are needed for keeping IL6R activation low. Finally, using hypertensive Dahl salt-sensitive rats, we showed that blunted β-adrenergic signaling is associated with NCX upregulation and enhanced IL6R signaling. We therefore propose a previously unrecognized protective role of β-adrenergic signaling, which is compromised in cardiac pathologies, in preventing IL6R overactivation under increased workload. A better understanding of these processes may contribute to refinement of therapeutic options for patients receiving β-blockers.
- Subject
- β-adrenergic signaling; isoprenaline; CaMKII; IL6R; cardiomyocyte; hypertrophy; hypertensive cardiomyopathy
- Identifier
- http://hdl.handle.net/1959.13/1489338
- Identifier
- uon:52685
- Identifier
- ISSN:2227-9059
- Rights
- x
- Language
- eng
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