Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias
Abstract
:1. Introduction
2. Results
2.1. Acute Upregulation of SERCA2a in the CASQ2 KO Mice Did Not Alter Expression of RyR2 and Phospholamban (PLB)
2.2. Acute Upregulation of SERCA2a in the CASQ2 KO Mice Exacerbated Ventricular Arrhythmias
2.3. Acute Upregulation of SERCA2a in the CASQ2 KO Mice Exacerbated Atrial Arrhythmias
2.4. Acute Upregulation of SERCA2a Increased Diastolic Ca Release in Intact CASQ2 KO Ventricular Myocytes
2.5. Acute Upregulation of SERCA2a Increased Diastolic Ca Release in Intact CASQ2 KO Atrial Myocytes
2.6. Acute SERCA2a Overexpression Increased Diastolic SR Ca Release in Permeabilized CASQ2 KO Myocytes
2.7. Changes in Gene Expression Induced by Acute SERCA2a Overexpression
3. Discussion
4. Materials and Methods
4.1. Generation of Double KO-TG Mouse Models
4.2. Electrocardiographic Recordings
4.3. Cardiomyocyte Isolation and Confocal Ca Imaging
4.4. Western Blots
4.5. RNA Extraction, Library Construction and Sequencing
4.6. RNA-seq Read Processing, Transcript Assembly, and Differential Expression
4.7. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AF | atrial fibrillation |
CAMKII | Ca2+/calmodulin-dependent protein kinase II |
Ca | calcium |
CASQ2 | calsequestrin 2 |
CICR | calcium-induced calcium release |
CPVT | catecholaminergic polymorphic ventricular tachycardia |
DAD | delayed afterdepolarizations |
DOX | doxycycline |
HF | heart failure |
KO | knock out |
ISO | isoproterenol |
PLB | phospholamban |
RyR2 | ryanodine receptor 2 |
SR | sarcoplasmic reticulum |
SERCA | SR Ca ATPase |
SCW | Spontaneous calcium waves |
WT | wild type |
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Down-Regulated | Gene | log2Fold Change | Adjusted p Value |
Fos | −2.7 | 1.17 × 10−28 | |
Vaultrc5 | −1.7 | 1.85 × 10−18 | |
Atf3 | −2.1 | 2.20 × 10−12 | |
Ppp1r13l | −1.7 | 2.24 × 10−12 | |
Egr1 | −1.5 | 2.75 × 10−11 | |
Grin2c | −1.9 | 5.97 × 10−11 | |
Nr4a3 | −1.8 | 6.86 × 10−11 | |
H2-T23 | −2 | 5.71 × 10−9 | |
H2-Eb1 | 5 | 5.90 × 10−8 | |
Rn45s | −2 | 5.47 × 10−7 | |
5730408K05Rik | −1.7 | 7.19 × 10−6 | |
Ifltd1 | −2.6 | 5.70 × 10−5 | |
Clcn1 | −1.5 | 0.004 | |
Prr5 | −1.6 | 0.004 | |
Rprl3 | −9.7 | 0.006 | |
Mir3113 | −1.5 | 0.01 | |
Nr4a1 | −1.9 | 0.028 | |
Up-regulated | Gene | log2Fold Change | Adjusted p Value |
Col4a6 | 4.5 | 3.61 × 10−29 | |
Zdhhc2 | 1.6 | 1.17 × 10−28 | |
Agt | 2.2 | 1.19 × 10−21 | |
Rps15a-ps6 | 1.5 | 0.001 | |
Selenbp2 | 2.4 | 0.004 |
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Liu, B.; Lou, Q.; Smith, H.; Velez-Cortes, F.; Dillmann, W.H.; Knollmann, B.C.; Armoundas, A.A.; Györke, S. Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias. Int. J. Mol. Sci. 2020, 21, 2535. https://doi.org/10.3390/ijms21072535
Liu B, Lou Q, Smith H, Velez-Cortes F, Dillmann WH, Knollmann BC, Armoundas AA, Györke S. Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias. International Journal of Molecular Sciences. 2020; 21(7):2535. https://doi.org/10.3390/ijms21072535
Chicago/Turabian StyleLiu, Bin, Qing Lou, Heather Smith, Florencia Velez-Cortes, Wolfgang H. Dillmann, Björn C. Knollmann, Antonis A. Armoundas, and Sándor Györke. 2020. "Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias" International Journal of Molecular Sciences 21, no. 7: 2535. https://doi.org/10.3390/ijms21072535