Matzer, Ingrid and Voglhuber, Julia and Kiessling, Mara and Djalinac, Natasa and Trummer-Herbst, Viktoria and Mabotuwana, Nishani and Rech, Lavinia and Holzer, Michael and Sossalla, Samuel and Rainer, Peter P. and Zirlik, Andreas and Ljubojevic-Holzer, Senka (2022) beta-Adrenergic Receptor Stimulation Maintains NCX-CaMKII Axis and Prevents Overactivation of IL6R-Signaling in Cardiomyocytes upon Increased Workload. BIOMEDICINES, 10 (7): 1648. ISSN , 2227-9059
Full text not available from this repository. (Request a copy)Abstract
Excessive beta-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 beta-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 beta-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 beta-adrenergic signaling is associated with NCX upregulation and enhanced IL6R signaling. We therefore propose a previously unrecognized protective role of beta-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 beta-blockers.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EXCHANGE CURRENT; INTERLEUKIN-6; HYPERTROPHY; IL-6; ISOPROTERENOL; CONTRACTION; TRANSCRIPTION; MYOCARDIUM; INDUCTION; MOUSE; beta-adrenergic signaling; isoprenaline; CaMKII; IL6R; cardiomyocyte; hypertrophy; hypertensive cardiomyopathy |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Feb 2024 06:33 |
| Last Modified: | 02 Feb 2024 06:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58329 |
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