Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling
Abstract
:1. Introduction
2. Results
2.1. LDH Release
2.2. mPTP Opening
2.3. Hemodynamic Parameters of the Heart and Arrhythmia Triggering
2.4. Molecular Analyses of Canonical and Non-Canonical Signalling Pathways of Necroptosis
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Animals and Experimental Groups
4.3. Experimental Myocardial I/R Protocol
4.4. Determination of LDH Activity
4.5. Isolation of Mitochondrial Fractions
4.6. Determination of mPTP Opening
4.7. SDS-PAGE and Immunoblotting
4.8. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADAMs | disintegrins and metalloproteinases |
AMPK | 5’ adenosine monophosphate-activated protein kinase |
BNIP3 | Bcl2 interacting protein 3 |
CaMKIIδ | Ca2+/calmodulin-dependent protein kinase II delta |
cMyBPc | cardiac myosin-binding protein c |
Drp1 | dynamin-related protein 1 |
FUNDC1 | FUN14 Domain Containing 1 |
GSK2399872A | GSK’872 |
HR | heart rate |
I/R | ischemia/reperfusion |
IL-1β | interleukin-1 beta |
JNK | c-Jun N-terminal kinase |
LDH | lactate dehydrogenase |
LVDP | left ventricular developed pressure |
LVEDP | LV end-diastolic pressure |
MLKL | mixed lineage kinase domain-like pseudokinase |
MnSOD | manganese superoxide dismutase |
mPTP | mitochondrial permeability transition pore |
NLRP3 | NOD-, LRR- and pyrin domain-containing protein 3 |
NOX2 | NADPH oxidase 2 |
PGAM5 | phosphoglycerate mutase family member 5 |
PLN | phospholamban |
RIP1 | receptor-interacting protein kinase 1 |
RIP3 | receptor-interacting protein kinase 3 |
ROS | reactive oxygen species |
RPP | rate pressure product |
TNF | tumour necrosis factor |
XO | xanthin oxidase |
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Stabilization | 10 min (re) Perfusion | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
LVDP (mmHg) | LVEDP (mmHg) | HR (BPM) | +dP/dt (mmHg/s) | −dP/dt (mmHg/s) | RPP (mmHg × BPM) | LVDP (mmHg) | LVEDP (mmHg) | HR (BPM) | +dP/dt (mmHg/s) | −dP/dt (mmHg/s) | RPP (mmHg × BPM) | |
Control | 74.6 ± 6.1 | 5.5 ± 1.1 | 264.0 ± 19.0 | 1591.6 ± 121.3 | 1225.9 ± 76.7 | 20,724.5 ± 1156.9 | 63.6 ± 7.6 | 3.4 ± 1.3 | 276.1 ± 7.2 | 1387.6 ± 163.4 | 1047.7 ± 128.6 | 17,529.6 ± 1978.9 |
Control + GSK’872 | 82.8 ± 3.7 | 4.0 ± 0.4 | 261.1 ± 21.9 | 1683.2 ± 78.3 | 1296.7 ± 59.5 | 21,595 ± 2009.8 | 79.7 ± 4.4 | 1.3 ± 0.6 | 281.0 ± 11.3 | 1655.9 ± 100.0 | 1343.0 ± 80.5 | 22,324.2 ± 1449.2 |
IR | 83.4 ± 4.7 | 3.5 ± 1.0 | 281.3 ± 3.4 | 1749.5 ± 106.6 | 1397.4 ± 66.6 | 23,873.7 ± 1519.0 | 26.9 ± 6.4 * | 31.7 ± 7.8 * | 228.1 ± 12.7 * | 376.6 ± 110.9 * | 342.9 ± 111.1 * | 6469.1 ± 1596.7 * |
IR + GSK’872 | 79.9 ± 3.1 | 3.2 ± 0.9 | 283.1 ± 7.2 | 1742.5 ± 70.0 | 1355.6 ± 48.5 | 23,352.9 ± 958.9 | 22.0 ± 7.4 * | 34.6 ± 9.5 * | 245.1 ± 30.6 | 376.8 ± 154.8 * | 319.5 ± 129.6 * | 5549.5 ± 2391.8 * |
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Horvath, C.; Young, M.; Jarabicova, I.; Kindernay, L.; Ferenczyova, K.; Ravingerova, T.; Lewis, M.; Suleiman, M.S.; Adameova, A. Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling. Int. J. Mol. Sci. 2021, 22, 7983. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983
Horvath C, Young M, Jarabicova I, Kindernay L, Ferenczyova K, Ravingerova T, Lewis M, Suleiman MS, Adameova A. Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling. International Journal of Molecular Sciences. 2021; 22(15):7983. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983
Chicago/Turabian StyleHorvath, Csaba, Megan Young, Izabela Jarabicova, Lucia Kindernay, Kristina Ferenczyova, Tanya Ravingerova, Martin Lewis, M. Saadeh Suleiman, and Adriana Adameova. 2021. "Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling" International Journal of Molecular Sciences 22, no. 15: 7983. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983