| Autor: |
Reyes Gaido OE; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Pavlaki N; Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA., Granger JM; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Mesubi OO; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Liu B; Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Lin BL; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Long A; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Walker D; Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA., Mayourian J; Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA., Schole KL; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Terrillion CE; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Nkashama LJ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Hulsurkar MM; Cardiovascular Research Institute and Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA., Dorn LE; Cardiovascular Research Institute and Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA., Ferrero KM; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Huganir RL; Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Müller FU; Institute of Pharmacology and Toxicology, University of Münster, Münster 48149, Germany., Wehrens XHT; Cardiovascular Research Institute and Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.; Departments of Medicine, Neuroscience, and Pediatrics, Center for Space Medicine, Baylor College of Medicine, Houston, TX 77030, USA., Liu JO; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Luczak ED; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Bezzerides VJ; Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA., Anderson ME; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.; Division of Biological Sciences and the Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA. |
| Abstrakt: |
Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and tractability for high-throughput screening. Using this tool, we carried out a drug repurposing screen (4475 compounds in clinical use) in human cells expressing constitutively active CaMKII. This yielded five previously unrecognized CaMKII inhibitors with clinically relevant potency: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. We found that ruxolitinib, an orally bioavailable and U.S. Food and Drug Administration-approved medication, inhibited CaMKII in cultured cardiomyocytes and in mice. Ruxolitinib abolished arrhythmogenesis in mouse and patient-derived models of CaMKII-driven arrhythmias. A 10-min pretreatment in vivo was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia, a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. At cardioprotective doses, ruxolitinib-treated mice did not show any adverse effects in established cognitive assays. Our results support further clinical investigation of ruxolitinib as a potential treatment for cardiac indications. |
