Mustroph, Juliano and Drzymalski, Marzena and Baier, Maria and Pabel, Steffen and Biedermann, Alexander and Memmel, Bernadette and Durczok, Melanie and Neef, Stefan and Sag, Can Martin and Floerchinger, Bernhard and Rupprecht, Leopold and Schmid, Christof and Zausig, York and Begis, Guillaume and Briand, Veronique and Ozoux, Marie-Laure and Tamarelle, Dorothee and Ballet, Veronique and Janiak, Philip and Beauverger, Philippe and Maier, Lars S. and Wagner, Stefan (2020) The oral Ca/calmodulin-dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure. ESC HEART FAILURE, 7 (5). pp. 2871-2883. ISSN 2055-5822,
Full text not available from this repository. (Request a copy)Abstract
Aims Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKII delta/CaMKII-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). Methods and results In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 +/- 3.7% (RA608) vs. 34.9 +/- 2.6% (vehicle), n = 9 vs.n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKII delta transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Conclusions RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in micein vivo.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RETICULUM CA2+ LEAK; DILATED CARDIOMYOPATHY; CAMKII; POTENTIATION; HYPERTROPHY; DYSFUNCTION; MYOCARDIUM; STRESS; MODEL; LOAD; Inhibition; Heart failure; Contractility; SR Ca leak; Arrhythmias |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Anästhesiologie Medicine > Lehrstuhl für Herz-, Thorax- und herznahe Gefäßchirurgie Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Mar 2021 07:41 |
| Last Modified: | 18 Mar 2021 07:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44193 |
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