Rapid ventricular pacing‐induced postconditioning attenuates reperfusion injury: effects on peroxynitrite, <scp>RISK</scp> and <scp>SAFE</scp> pathways

Pipicz, Márton; Varga, Zoltán V.; Kupai, Krisztina; Gáspár, Renáta; Kocsis, Gabriella F.; Csonka, Csaba; Csont, Tamás

doi:10.1111/bph.13154

Cited by 15 publications

(11 citation statements)

References 59 publications

(66 reference statements)

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“…Tissue lipid accumulation is often associated with increased nitro-oxidative stress in various organs, therefore we have also investigated the effect of isolated hypercholesterolemia on nitro-oxidative stress in the liver. Our findings showing elevated hepatic nitro-oxidative stress due to isolated hypercholesterolemia is in line with our own observations made previously in the heart [ 32 , 37 , 42 ].…”

Section: Discussionsupporting

confidence: 93%

“…To further characterize hepatic damage induced by isolated hypercholesterolemia 3-nitrotyrosine level was measured in liver samples as a marker of tissue nitro-oxidative stress using ELISA (Cayman Chemical, Ann Arbor, MI, USA) as described previously [ 38 , 41 , 42 ]. Briefly, homogenates were incubated overnight with nitrotyrosine acetylcholinesterase tracer and anti-nitrotyrosine rabbit IgG in microplates pre-coated with mouse anti-rabbit IgG.…”

Section: Methodsmentioning

confidence: 99%

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Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas

et al. 2017

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BackgroundLipid accumulation in the liver and pancreas is primarily caused by combined hyperlipidemia. However, the effect of isolated hypercholesterolemia without hypertriglyceridemia is not fully described. Therefore, our aim was to investigate whether hypercholesterolemia alone leads to alterations both in hepatic and pancreatic lipid panel and histology in rats.MethodsMale Wistar rats were fed with 2% cholesterol +0.25% cholate-supplemented diet or standard chow for 12 weeks. Blood was collected at weeks 0, 4, 8 and 12 to measure serum cholesterol and triglyceride levels. At week 12, both the pancreas and the liver were isolated for further histological and biochemical analysis. Hepatic and plasma fatty acid composition was assessed by gas chromatography. Expression of mRNA of major enzymes involved in saturated/unsaturated fatty acid synthesis was analyzed by qPCR. In separate experiments serum enzyme activities and insulin levels were measured at week 9.ResultsAt week 12, rats fed with 2% cholesterol +0.25% cholate-supplemented diet were characterized by elevated serum cholesterol (4.09 ± 0.20 vs. 2.89 ± 0.22 mmol/L, *p < 0.05) while triglyceride (2.27 ± 0.05 vs. 2.03 ± 0.03 mmol/L) and glucose levels (5.32 ± 0.14 vs. 5.23 ± 0.10 mmol/L) remained unchanged. Isolated hypercholesterolemia increased hepatic lipid accumulation, hepatic cholesterol (5.86 ± 0.22 vs. 1.60 ± 0.15 ng/g tissue, *p < 0.05) and triglyceride contents (19.28 ± 1.42 vs. 6.78 ± 0.71 ng/g tissue, *p < 0.05), and hepatic nitrotyrosine level (4.07 ± 0.52 vs. 2.59 ± 0.31 ng/mg protein, *p < 0.05). The histology and tissue lipid content of the pancreas was not affected. Serum total protein level, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities remained unchanged in response to isolated hypercholesterolemia while serum alkaline phosphatase activity (ALP) significantly increased. Plasma insulin levels did not change in response to isolated hypercholesterolemia suggesting an intact endocrine function of the pancreas. Isolated hypercholesterolemia caused a significantly increased hepatic and serum fatty acid level associated with a marked alteration of fatty acid composition. Hepatic expression of Δ9-desaturase (SCD1) was increased 4.92×, while expression of Δ5-desaturase and Δ6-desaturase were decreased (0.447× and 0.577×, respectively) due to isolated hypercholesterolemia.ConclusionsIsolated hypercholesterolemia leads to hepatic steatosis and marked alterations in the hepatic lipid profile without affecting the pancreas. Altered fatty acid profile might mediate harmful effects of cholesterol in the liver.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas

et al. 2017

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“…Moreover, PPC induced a remarkable reduction in the CK and LDH levels. Although evaluations of hemodynamics have seldom been conducted, the protective effects of PPC were reported by us and other researchers [1,2,30,34]. However, the pathways involved in PPC-mediated protection and the interaction between PPC and body homeostasis have not been completely elucidated.…”

Section: Discussionmentioning

confidence: 97%

Discrepancy in calcium release from the sarcoplasmic reticulum and intracellular acidic stores for the protection of the heart against ischemia/reperfusion injury

Khalaf

Babiker

2016

J Physiol Biochem

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We and others have demonstrated a protective effect of pacing postconditioning (PPC) against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection are not completely clear. In the present study, we evaluated the effects of calcium release from the sarcoplasmic reticulum (SR) and the novel intracellular acidic stores (AS). Isolated rat hearts (n = 6 per group) were subjected to coronary occlusion followed by reperfusion using a modified Langendorff system. Cardiac hemodynamics and contractility were assessed using a data acquisition program, and cardiac injury was evaluated by creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Hearts were subjected to 30 min of regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery, followed by 30 min of reperfusion. The hearts were also subjected to PPC (3 cycles of 30 s of left ventricle (LV) pacing alternated with 30 s of right atrium (RA) pacing) and/or were treated during reperfusion with agonists or antagonists of release of calcium from SR or AS. PPC significantly (P < 0.05) normalized LV, contractility, and coronary vascular dynamics and significantly (P < 0.001) decreased heart enzyme levels compared to the control treatments. The blockade of SR calcium release resulted in a significant (P < 0.01) recovery in LV function and contractility and a significant reduction in CK and LDH levels (P < 0.01) when applied alone or in combination with PPC. Interestingly, the release of calcium from AS alone or in combination with PPC significantly improved LV function and contractility (P < 0.05) and significantly decreased the CK and LDH levels (P < 0.01) compared to the control treatments. An additive effect was produced when agonism of calcium release from AS or blockade of calcium release from the SR was combined with PPC. Calcium release from AS and blockade of calcium release from the SR protect the heart against I/R. Combining calcium release from acidic stores or blockade of calcium release from the SR with PPC produced a synergistic protective effect.

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“…Here we show that PPC induced cardiac protection also involves enhanced activation of ERK1/2 and Akt (Fig 5). In contrast however Pipicz and his group have demonstrated that rapid ventricular pacing does not induce ERK1/2 activation [52]. The reason behind this discrepancy is however not clear.…”

Section: Discussionmentioning

confidence: 97%

The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

2016

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BackgroundAccumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1–7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury.ObjectiveThe objective of this study was to investigate the role of angiotensin converting enzyme (ACE)—chymase—angiotensin II (Ang II)—angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection.MethodsIsolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels.ResultsCardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components of the reperfusion injury salvage kinase (RISK) pathway.ConclusionsThis study demonstrate a novel role of endogenously produced Ang II in mediating I/R injury and highlights the significance of AT1 signaling in PPC mediated cardiac protection in isolated rodents hearts ex vivo. The interaction between Ang II-AT1 and PPC appears to involve alterations in the activation state of ERK1/2 and Akt components of the RISK pathway.

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Rapid ventricular pacing‐induced postconditioning attenuates reperfusion injury: effects on peroxynitrite, RISK and SAFE pathways

Cited by 15 publications

References 59 publications

Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas

Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas

Discrepancy in calcium release from the sarcoplasmic reticulum and intracellular acidic stores for the protection of the heart against ischemia/reperfusion injury

The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

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