Stabilizing Microtubules Decreases Myocardial Ischaemia-Reperfusion Injury

Wang, Q; Hy, You; Li, Jian; Zy, Yang

doi:10.1177/147323001103900513

Cited by 5 publications

(10 citation statements)

References 24 publications

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“…Furthermore, pretreatment with 1 μ m paclitaxel was shown to reduce both the infarct size after ischaemia–reperfusion and the incidence of ventricular tachycardia during ischaemia in isolated rat hearts submitted to partial occlusion of the left main coronary artery (Cao et al . ). These results were later extended to show, in the same model, an improvement in functional recovery after 15 min of regional ischaemia followed by reperfusion (Xiao et al .…”

Section: Discussionmentioning

confidence: 97%

“…, ; Cao et al . ), successful ligation was indicated by a >25% reduction in coronary flow, which may add variability to the results. Furthermore, we have demonstrated that treatment with paclitaxel induced, in our isolated cell model, a deleterious higher increase in cytosolic Ca 2+ levels during ischaemia and, at the highest concentration, a steep reduction during reoxygenation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…, ; Cao et al . ). Th eresults were compared with those obtained in six control hearts submitted only to ischaemia–reperfusion with no additional intervention.…”

Section: Methodsmentioning

confidence: 97%

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Microtubule stabilization with paclitaxel does not protect against infarction in isolated rat hearts

Rodríguez‐Sinovas

Abad

Sánchez

et al. 2014

Experimental Physiology

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New Findings r What is the central question of this study?The microtubule network is disrupted during myocardial ischaemia-reperfusion injury. It was suggested that prevention of microtubule disruption with paclitaxel might reduce cardiac infarct size; however, the effects on infarction have not been studied. r What is the main finding and its importance?Paclitaxel caused a reduction in microtubule disruption and cardiomyocyte hypercontracture during ischaemia-reperfusion. However, it induced a greater increase in cytosolic calcium, which may explain the lack of effect against infarction that we have seen in isolated rat hearts. The large increase in perfusion pressure induced by paclitaxel in this model may have clinical implications, because detrimental effects of the drug were reported after its clinical application.Microtubules play a major role in the transmission of mechanical forces within the myocardium and in maintenance of organelle function. However, this intracellular network is disrupted during myocardial ischaemia-reperfusion. We assessed the effects of prevention of microtubule disruption with paclitaxel on ischaemia-reperfusion injury in isolated rat cardiomyocytes and hearts. Isolated rat cardiomyocytes were submitted to normoxia (1 h) or 45 min of simulated ischaemia (pH 6.4, 0% O 2 , 37°C) and reoxygenation, without or with treatment with the microtubule stabilizer, paclitaxel (10 −5 m), or the inhibitor of microtubule polymerization, colchicine (5 × 10 −6 m). Simulated ischaemia leads to microtubule disruption before the onset of ischaemic contracture. Paclitaxel attenuated both microtubule disruption and the incidence of hypercontracture, whereas treatment with colchicine mimicked the effects of simulated ischaemia and reoxygenation. In isolated normoxic rat hearts, treatment with paclitaxel induced concentration-dependent decreases in heart rate and left ventricular developed pressure and increases in perfusion pressure. Despite protection against hypercontracture, paclitaxel pretreatment did not modify infarct size (60.37 ± 2.27% in control hearts versus 58.75 ± 10.25, 55.44 ± 10.32 and 50.06 ± 10.14% after treatment with 10 −6 , 3 × 10 −6 and 10 −5 m of paclitaxel) after 60 min of global ischaemia and reperfusion in isolated rat hearts. Lack of protection was correlated with a higher increase in cytosolic calcium levels during simulated ischaemia in cardiomyocytes treated with paclitaxel (2.32 ± 0.15 versus 1.13 ± 0.16 a.u. in the presence or A. Rodríguez-Sinovas and E. Abad contributed equally to this work. A. Rodríguez-Sinovas and others absence of 10 −6 m paclitaxel, respectively, P < 0.05), but not with changes in aortic reactivity. In conclusion, microtubule stabilization with paclitaxel reduces hypercontracture in isolated rat cardiomyocytes but does not protect against infarction in isolated rat hearts.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Microtubule stabilization with paclitaxel does not protect against infarction in isolated rat hearts

Rodríguez‐Sinovas

Abad

Sánchez

et al. 2014

Experimental Physiology

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“…Destruction of the internal architecture worsens I/R injuries and leads to apoptosis. [53], [56], [57] During ischemia, all elements of the cytoskeleton are affected, but with different kinetics. [54], [55] Moreover, the accumulation of osmotically active particles, including lactate, sodium, inorganic phosphate and creatine, induces cellular oedema.…”

Section: Structural and Functional Modificationsmentioning

confidence: 99%

“…Ischemia deconstructs the cytoskeleton. [53]- [56] The high intracellular concentrations of Ca 2+ that are associated with ischemia activate multiple phosphorylases and proteases that disassemble and degrade the cytoskeleton, thereby eliminating the functions that rely on its integrity, such as phagocytosis, exocytosis, myofilament contraction, intercellular communication and cell anchorage. Destruction of the internal architecture worsens I/R injuries and leads to apoptosis.…”

Section: Structural and Functional Modificationsmentioning

confidence: 99%