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An invited review following the Soujinkai Young Investigator Award : stabilization of ryr2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension

Medical Science & Innovation Volume 70 Issue 3-4 Page 19-26
published_at 2023-12
A050070000301.pdf
[fulltext] 3.07 MB
Title
An invited review following the Soujinkai Young Investigator Award : stabilization of ryr2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension
Abstract
Right ventricular (RV) dysfunction and its linked arrhythmias play a crucial role in determining the prognosis of pulmonary arterial hypertension (PAH). Our paper aimed to explore the potential protective effects of direct pharmacological intervention in the RV muscle using dantrolene (DAN), a stabilizer of the cardiac ryanodine receptor (RyR2), against RV dysfunction and arrhythmia in a rat model of monocrotaline (MCT)-induced PAH. To induce PAH, male 8-week-old Sprague-Dawley rats received MCT injections. The study also assessed the induction of ventricular tachycardia (VT) by catecholamines, examining RyR2-mediated Ca^{2+} release properties in isolated cardiomyocytes. Additionally, a pulmonary artery-banding model was established to evaluate the independent effects of chronic pressure overload on RV morphology and function. In the MCT-induced PAH rat model, findings revealed RV hypertrophy, dilation, and functional decline, resulting in 0% survival rate two months post-MCT induction. Conversely, chronic DAN treatment demonstrated improvements in these RV parameters and an 80% increase in survival. Furthermore, chronic DAN treatment prevented the dissociation of calmodulin from RyR2, inhibiting Ca^{2+} sparks and spontaneous Ca^{2+} transients in MCT-induced hypertrophied RV cardiomyocytes. Epinephrine induced VT in over 50% of rats with MCT-induced PAH, while chronic DAN treatment achieved complete suppression of VT. The paper concludes that stabilizing RyR2 with DAN holds promise as a novel therapeutic approach against the development of RV dysfunction and fatal arrhythmias associated with PAH.
Creators Tanaka Shinji
Creators Yamamoto Takeshi
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Creators Kobayashi Shigeki
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Creators Yano Masafumi
Source Identifiers
Creator Keywords
calmodulin ryanodine receptor pulmonary arterial hypertension dantrolene ventricular arrhythmia
Languages eng
Resource Type departmental bulletin paper
Publishers Yamaguchi University School of Medicine
Date Issued 2023-12
File Version Version of Record
Access Rights open access