To investigate the role of high concentrations of dl-3-hydroxybutyrate (DL-3-HB) in preventing heart damage after prolonged fasting, infarct size and the incidence of apoptosis caused by ischemia-reperfusion were determined in four groups of Wistar rats. Fed rats (+/-DL-3-HB group) and fasted rats (+/-DL-3-HB group) were subjected to 30 min of left coronary artery occlusion and 120 min of reperfusion. DL-3-HB was administered intravenously 60 min before the coronary artery occlusion. Infarct size, defined by triphenylyetrazolium chloride (TTC) staining, was reduced from 72 +/- 3% (fed group), 75 +/- 5% (fed + DL-3-HB group), and 70 +/- 5% (fasting group), respectively, to 26 +/- 4% (P < 0.01 vs. fasting + DL-3-HB group). Apoptosis, as defined by single-stranded DNA staining, was significantly reduced in the subendocardial region in the fasting + DL-3-HB group (9 +/- 2%) compared with the other groups (39 +/- 6% in the fed group, 37 +/- 5% in the fed + DL-3-HB group, and 34 +/- 3% in the fasting group; P < 0.01). In addition, levels of ATP in the fasting + DL-3-HB group were significantly higher compared with other groups after 30 min of ischemia and 120 min of reperfusion (P < 0.01). In conclusion, the present study demonstrates that high concentrations of DL-3-HB reduces myocardial infarction size and apoptosis induced by ischemia-reperfusion, possibly by providing increased energy substrate to the fasted rat myocardium.

The cytoprotective effects of SWOP are dependent on PTP activation state and may involve upregulation of Bcl-2 expression.

Abstract. It has been reported that RhoA activation and Rho-kinase (ROCK) expression are increased in chronic hypoxic lungs, and the long-term inhibition of ROCK markedly improves the survival of patients with pulmonary arterial hypertension (PAH). However, whether Rho-kinase α (ROCK2) participates in regulation of the growth of pulmonary arterial endothelial cells (PAECs) remains unknown. The aim of the present study was to investigate the effect of hypoxia on the proliferation of PAECs and the role of ROCK2 in the underlying mechanism. The results of western blotting and reverse transcription-quantitative polymerase chain reaction analysis showed that hypoxia increased the activity and expression of ROCK2 in PAECs, and the stimulating effects of hypoxia on the proliferation of PAECs were attenuated by either the ROCK inhibitor Y27632 or transfection with ROCK2 small interfering RNA. Moreover, analysis of cyclin A and cyclin D1 mRNA expression indicated that ROCK2 mediates the cell cycle progression promoted by hypoxia. These results indicate that hypoxia promotes the proliferation of pulmonary arterial endothelial cells via activation of the ROCK2 signaling pathway. IntroductionPulmonary arterial hypertension (PAH) is a fatal condition characterized by increased pulmonary vascular resistance and finally leading to right heart failure and mortality (1,2). Endothelial injury, prolonged vasoconstriction and the proliferation and migration of vascular smooth muscle cells (VSMCs), are causes of increased pulmonary vascular resistance (3). Multiple pharmacological agents, such as vasodilators and anticoagulants, have been developed for the treatment of PAH; however, the long-term prognosis of patients with severe PAH remains poor (3). Therefore, there is an urgent requirement for the development of more effective treatments for PAH.Rho-kinase (ROCK) is a member of the serine/threonine kinase family that is an important downstream effector of the small GTP-binding protein RhoA. The Rho/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation and migration (4,5). There are two isoforms of ROCK, namely ROCK1 (Rho-kinase β) and ROCK2 (Rho-kinase α) (6). ROCK1 and ROCK2 are highly homologous with regard to amino acid sequence and kinase domains, sharing ~65% homology in amino acid sequence and 92% homology in their kinase domains (6). Although the two isoforms are ubiquitously expressed in invertebrates and vertebrates, ROCK1 is expressed mainly in circulating inflammatory cells and ROCK2 is expressed in vascular cells (7,8). Homozygous ROCK1-deficient mice show open eyelids at birth and omphalocele, whereas homozygous ROCK2-deficient mice die embryonically because of placental dysfunction, suggesting that ROCK1 and ROCK2 mediate different functions in different types of cells (9,10). To date, to the best of our knowledge, whether ROCK is responsible for the growth of pulmonary arterial endothelial cells (PAECs) has not yet been evaluated.The present ...

Despite major advances in treating patients with coronary heart disease, reperfusion injury is still considered to be a major problem, especially in surgical settings. Here, we demonstrate the protective effects of a novel bisindolylmaleimide derivative, MS1 (2-[1-(3-aminopropyl)indol-3-yl]-3-(indol-3-yl)-N-methylmaleimide), against reperfusion injury of the heart. After anesthesia and artificial ventilation, Wistar rats were subjected to 30 min of left coronary artery occlusion followed by 120 min of reperfusion with or without treating the rats with MS1 (2.25 mumol.L-1.kg-1) before left coronary artery occlusion. Compared with the untreated hearts, MS1 treatment significantly reduced myocardial infarct size (35.1% +/- 3% vs. 75.5% +/- 5%, p < 0.001), reduced prevalence of apoptotic cells (2.6% +/- 0.5% vs. 12.2% +/- 2.1%, p < 0.001), prevented mitochondrial swelling and cytochrome c release, inhibited downregulation of antiapoptotic protein Bcl-2 expression, and suppressed caspase-3 activation. In contrast, pretreatment with atractyloside, a mitochondrial permeability transition pore opener, abolished the protective effects of MS1. In conclusion, MS1 inhibits pathologic opening of permeability transition pores and protects the heart against reperfusion injury and pathologic apoptosis.

These results altogether indicate the efficacy of this compound in protecting the myocardium against reperfusion injury and thus making this drug a clinically useful tool in patients undergoing reperfusion after cardiac surgeries.