Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

• Published in: International journal of molecular sciences 2020-04, Vol.21 (7), p.2535
• Main Authors: Liu, Bin, Lou, Qing, Smith, Heather, Velez-Cortes, Florencia, Dillmann, Wolfgang H, Knollmann, Björn C, Armoundas, Antonis A, Györke, Sándor
• Format: Article
• Language: English
• Subjects: Ablation; Action Potentials; and ec-coupling 4; Animals; arrhythmia 1; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Ca2+-transporting ATPase; Caffeine; Calcium; calcium channel 2; Calcium Signaling; calcium signaling 3; Calsequestrin; Calsequestrin - genetics; Cardiac arrhythmia; Cardiac muscle; Cells, Cultured; Confocal microscopy; Coronary artery disease; Doxycycline; EKG; Genes; Heart Atria - cytology; Heart Atria - metabolism; Heart Atria - physiopathology; Heart diseases; Heart Ventricles - cytology; Heart Ventricles - metabolism; Heart Ventricles - physiopathology; Hyperactivity; Male; Mice; Mice, Inbred C57BL; Mutation; Myocytes; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Transcriptome; Transgenic mice; Up-Regulation; Ventricle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21072535

Ryanodine receptor 2 (RyR2) and SERCA2a are two major players in myocyte calcium (Ca) cycling that are modulated physiologically, affected by disease and thus considered to be potential targets for cardiac disease therapy. However, how RyR2 and SERCA2a influence each others' activities, as well as the primary and secondary consequences of their combined manipulations remain controversial. In this study, we examined the effect of acute upregulation of SERCA2a on arrhythmogenesis by conditionally overexpressing SERCA2a in a mouse model featuring hyperactive RyR2s due to ablation of calsequestrin 2 (CASQ2). CASQ2 knock-out (KO) mice were crossbred with doxycycline (DOX)-inducible SERCA2a transgenic mice to generate KO-TG mice. In-vivo ECG studies have shown that induction of SERCA2a (DOX+) overexpression markedly exacerbated both ventricular and atrial arrhythmias in vivo, compared with uninduced KO-TG mice (DOX-). Consistent with that, confocal microscopy in both atrial and ventricular myocytes demonstrated that conditional upregulation of SERCA2a enhanced the rate of occurrence of diastolic Ca release events. Additionally, deep RNA sequencing identified 17 downregulated genes and 5 upregulated genes in DOX+ mice, among which Ppp1r13l, Clcn1, and Agt have previously been linked to arrhythmias. Our results suggest that conditional upregulation of SERCA2a exacerbates hyperactive RyR2-mediated arrhythmias by further elevating diastolic Ca release.