scholarly journals Endoplasmic Reticulum Stress/Ca2+-Calmodulin-Dependent Protein Kinase/Signal Transducer and Activator of Transcription 3 Pathway Plays a Role in the Regulation of Cellular Zinc Deficiency in Myocardial Ischemia/Reperfusion Injury

2022 ◽  
Vol 12 ◽  
Author(s):  
Huanhuan Zhao ◽  
Dan Liu ◽  
Qiumei Yan ◽  
Xiyun Bian ◽  
Jing Yu ◽  
...  
Keyword(s):  
Er Stress ◽  
Zinc Deficiency ◽  
Calcium Concentration ◽  
Ischemia Reperfusion ◽  
Zinc Homeostasis ◽  
Dependent Protein Kinase ◽  
Stat3 Phosphorylation ◽  
Dependent Protein ◽  
Myocardial Ischemia Reperfusion ◽  
Cellular Zinc

Zinc homeostasis has been known to play a role in myocardial ischemia/reperfusion (I/R) injury, but the precise molecular mechanisms regulating the expression of ZIP transporters during reperfusion are still unclear. The aim of this study was to determine whether ER Stress/CaMKII/STAT3 pathway plays a role in the regulation of cellular zinc homeostasis. Zinc deficiency increased mRNA and protein expressions of the ER stress relevant markers Chop and Bip, and STAT3 phosphorylation in H9c2 or HL-1 cells, an effect that was abolished by ZnCl2. ER calcium concentration [(Ca2+)ER] was decreased and cytosolic calcium concentration [(Ca2+)I] was increased at the condition of normoxia or ischemia/reperfusion, indicating that zinc deficiency triggers ER stress and Ca2+ leak. Further studies showed that upregulation of STAT3 phosphorylation was reversed by Ca2+ chelator, indicating that intracellular Ca2+ is important for zinc deficiency-induced STAT3 activation. In support, zinc deficiency enhanced ryanodine receptors (RyR), a channel in the ER that mediate Ca2+ release, and Ca2+-calmodulin-dependent protein kinase (CaMKII) phosphorylation, implying that zinc deficiency provoked Ca2+ leak from ER via RyR and p-CaMKII is involved in STAT3 activation. Moreover, inhibition of STAT3 activation blocked zinc deficiency induced ZIP9 expression, and resulted in increased Zn2+ loss in cardiomyocytes, further confirming that STAT3 activation during reperfusion promotes the expression of ZIP9 zinc transporter to correct the imbalance in zinc homeostasis. In addition, suppressed STAT3 activation aggravated reperfusion injury. These data suggest that the ER Stress/CaMKII/STAT3 axis may be an endogenous protective mechanism, which increases the resistance of the heart to I/R.

Ca2+/Calmodulin-Dependent Protein Kinase II Regulation by Inhibitor 1 of Protein Phosphatase 1 Protects Against Myocardial Ischemia–Reperfusion Injury

2019 ◽  
Vol 24 (5) ◽  
pp. 460-473
Author(s):  
Jin Yu ◽  
Yun Chen ◽  
Mengting Xu ◽  
Linlin Sun ◽  
Huiqin Luo ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Protein Phosphatase 1 ◽  
Myocardial Infarct Size ◽  
Dependent Protein Kinase ◽  
Ldh Activity ◽  
Dependent Protein ◽  
Myocardial Ischemia Reperfusion ◽  
Pathological Structure

Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) plays a vital role in cardiovascular system. However, the potential protective role of inhibitor 1 of protein phosphatase 1 (I1PP1), which can regulate CaMKII, on myocardial ischemia–reperfusion (I/R) injury remains unknown. In the present study, expression of CaMKIIδ variants was detected by quantitative real-time polymerase chain reaction. I1PP1 was overexpressed by pericardial injection of recombinant adenovirus. Two weeks later, rats were subjected to left anterior descending ligation for 30 minutes followed by reperfusion. Myocardial infarct size was assessed by Evans blue/triphenyl tetrazolium chloride staining. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) activity as well as myocardial pathological structure were detected. CaMKII activity was evaluated by phosphorylation of phospholamban (PLB) and oxidation of CaMKII. Expression of dynamin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) in the mitochondria was measured by Western blot. We found that CaMKIIδA and CaMKIIδB expression decreased, while the expression of CaMKIIδC increased after myocardial I/R. Moreover, after 30-minute ischemia followed by 6 hours of reperfusion, I1PP1 overexpression reduced myocardial infarct size, decreased serum CK and LDH activity, ameliorated myocardial pathological structure, inhibited PLB phosphorylation at Thr17, suppressed CaMKII oxidation, elevated CaMKIIδA and CaMKIIδB variants but reduced CaMKIIδC variants, attenuated myocardial oxidative stress, improved myocardial mitochondrial ultrastructure, increased mitochondrial number and mitochondrial DNA copy number, and decreased DRP1 but increased OPA1 protein expression from the mitochondria in rats. Thus, I1PP1 regulated CaMKII, protected mitochondrial function, reduced oxidative stress, and attenuated myocardial I/R injury.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

Abstract 16598: The Role of Paraoxonase 2 in Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jingyuan Li ◽  
Victor R Grijalva ◽  
Srinivasa T Reddy ◽  
Mansoureh Eghbali
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objectives: Paraoxonases (PON) gene family consists of three proteins PON1, PON2, and PON3. PON2 is an intracellular membrane-associated protein that is widely expressed in vascular cells and many tissues. At the subcellular level, PON2 is localized to both the ER and mitochondria, and protects against oxidative stress. Hypothesis: The aim of this study was to investigate the role of PON2 in myocardial ischemia reperfusion injury. Methods: PON2 deficient (PON2-/-) and WT male mice were subjected to in-vivo ischemia/reperfusion injury. The left anterior descending coronary artery was occluded for 30 min followed by 24 hr of reperfusion. The infarct size, mitochondrial calcium retention capacity (CRC) and reactive oxygen species (ROS) generation were measured. The expression of C/EBP homologous protein (CHOP), GSK3b and phosphate GSK3b protein were examined by Western Blot. The number of animals was 5-7/group and data were expressed as mean±SEM. T test were used for statistical analysis. Probability values <0.05 were considered statistically significant. Results: The infarct size was ~2 fold larger in PON2 deficient mice compared to WT mice (p<0.05). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to calcium overload was much lower in PON2-/- mice compared with WT mice (173±19 in PON2-/-, 250±41 in WT, nmol/mg-mitochondrial protein, p<0.05). The ROS production was ~2 fold higher in isolated cardiac mitochondria from PON2-/- mice compared with WT mice (p<0.05). ER stress protein CHOP increased significantly in PON2-/- mice compared to WT mice (normalized to WT: 1±0.05 in WT, 1.66±0.08 in PON2-/-, p<0.001). Phospho-GSK3b level was significantly downregulated in in PON2-/- mice compared to WT mice (pGSK3b/GSK3b normalized to WT: 1±0.06 in WT 0.67±0.08 in PON2-/-, p<0.05). Conclusions: PON2 regulates myocardial ischemia/reperfusion injury via inhibiting the opening of mPTP, which is associated with reduced mitochondria ROS production, deactivation of ER stress signaling CHOP and GSK3b.

ID: 60: ZINC DEFICIENCY PRIMES THE LUNG FOR VENTILATOR INDUCED LUNG INJURY

2016 ◽  
Vol 64 (4) ◽  
pp. 973.1-973
Author(s):  
J Englert ◽  
F Boudreault ◽  
M Pinilla-Vera ◽  
C Isabelle ◽  
A Arciniegas ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Zinc Deficiency ◽  
Zinc Homeostasis ◽  
Adaptive Responses ◽  
Ventilator Induced Lung Injury ◽  
Human Lung Cells ◽  
Zinc Levels ◽  
Cellular Zinc

Mechanical ventilation is a necessary intervention to support patients with lung injury and the acute respiratory distress syndrome (ARDS), but can also exacerbate injury through mechanical stress-activated signaling pathways. We show that stretch applied to cultured human lung cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent anti-oxidant and cyto-protective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by injurious mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc binding transcription factor MTF-1. We further show that dietary zinc-deficiency in mice potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients with ARDS compared to healthy and non-ARDS ICU controls, as well as to other critically ill patients without ARDS. Taken together, our findings identify a novel adaptive response of the lung to stretch mediated by metallothionein and zinc. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating ventilator-induced lung injury, and identify zinc and metallothionein as targets for developing lung-protective interventions in patients requiring mechanical ventilation.

P5381Lack of sirtuin 5 aggravates myocardial ischemia reperfusion injury

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C N Witt ◽  
C Koentges ◽  
K Pfeil ◽  
L Vogelbacher ◽  
T Pusdrowski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Oxidative Stress ◽  
Heart Perfusion ◽  
Dependent Protein ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Developed Pressure

Abstract Sirtuin 5 (SIRT5) is a mitochondrial NAD+-dependent protein deacylase which regulates the enzymatic activity of numerous mitochondrial proteins due to increased succinylation and malonylation, including enzymes of energy substrate oxidation and mitochondrial antioxidant enzymes. Since energy depletion and mitochondrial oxidative stress contribute to myocardial IR injury, it was our objective to evaluate the potential role of SIRT5 in IR injury. In regular Langendorff heart perfusions, 8 week-old cardiomyocyte-selective SIRT5−/− mice showed no difference in LV developed pressure or dp/dt max compared to wildtype mice. However, recovery of LV developed pressure and dp/dt max following 25 min of ischemia was lower by 34% and 20% in SIRT5−/− mice compared to WT mice, respectively. In contrast, postischemic recovery of cardiac function was not impaired and even improved in mice with cardiomyocyte-selective overexpression of SIRT5 compared to WT mice undergoing IR. Mitochondrial H2O2 generation was significantly increased in SIRT5−/− mice compared to WT mice following IR, and mitochondria-targeted antioxidant treatments (MnTBAP or SS-31) during heart perfusion completely normalized recovery of contractile parameters in SIRT5−/− mice following IR. In conclusion, SIRT5 is not required to maintain cardiac function under physiological conditions. However, lack of SIRT5 aggravates myocardial IR injury, likely by increasing mitochondrial oxidative stress. SIRT5 agonism may thus represent a potential therapeutic strategy to attenuate myocardial IR injury.

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