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

Abstract

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.

Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia

“…Owing to its potent anti-mitotic properties, paclitaxel has been extensively used for the treatment of cancers, in particular ovarian, breast and lung cancers ( Jordan and Wilson, 2004 ). It has also been evaluated on cellular and animal models in other pathological contexts, such as myocardial infarction and neurodegenerative diseases ( Baas and Ahmad, 2013 ; Rodríguez-Sinovas et al, 2015 ; Xiao et al, 2011 ). We do not consider this drug as a candidate for therapeutic use in FA due to its toxicity, leading to a narrow therapeutic window.…”

Human Lysyl Oxidase Over-Expression Enhances Baseline Cardiac Oxidative Stress but Does Not Aggravate ROS Generation or Infarct Size Following Myocardial Ischemia-Reperfusion

“…The release of LDH was analyzed in the coronary effluent by spectrophotometry at 340 nm, as previously described [ 18 ]. At the end of reperfusion cardiac slices were stained with 2,3,5-triphenyltetrazolium to establish the infarct size.…”

“…The size of the necrotic area in each slice and total slice area were calculated using Image-Pro Plus (Media Cybernetics Inc., Rockville, MD, USA) software. Final infarct size was expressed as percentage of total cardiac weight taking into consideration the individual weights of each slice [ 18 ].…”

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology

“…This state rapidly stimulates glycolysis in cardiomyocytes, providing anaerobic ATP and lactate in a process controlled by HIF-1α [ 302 ]. In addition, cellular microtubules, playing a pivotal role in the transmission of mechanical forces within the myocardium, are disorganized in hypoxic conditions [ 303 ]. Their breakdown level determines cardiomyocyte viability [ 304 ].…”