Yoshimune Hiramoto

AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress

ABSTRACT Oxygen deprivation leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), causing ER stress. Under conditions of ER stress, inhibition of protein synthesis and up-regulation of ER chaperone expression reduce the misfolded proteins in the ER. AMP-activated protein kinase (AMPK) is a key regulatory enzyme involved in energy homeostasis during hypoxia. It has been shown that AMPK activation is associated with inhibition of protein synthesis via phosphorylation of elongation factor 2 (eEF2) in cardiomyocytes. We therefore examined whether AMPK attenuates hypoxia-induced ER stress in neonatal rat cardiomyocytes. We found that hypoxia induced ER stress, as assessed by the expression of CHOP and BiP and cleavage of caspase 12. Knockdown of CHOP or caspase 12 through small interfering RNA (siRNA) resulted in decreased expression of cleaved poly(ADP-ribose) polymerase following exposure to hypoxia. We also found that hypoxia-induced CHOP expression and cleavage of caspase 12 were significantly inhibited by pretreatment with 5-aminoimidazole-4-carboxyamide-1-β-d-ribofuranoside (AICAR), a pharmacological activator of AMPK. In parallel, adenovirus expressing dominant-negative AMPK significantly attenuated the cardioprotective effects of AICAR. Knockdown of eEF2 phosphorylation using eEF2 kinase siRNA abolished these cardioprotective effects of AICAR. Taken together, these findings demonstrate that activation of AMPK contributes to protection of the heart against hypoxic injury through attenuation of ER stress and that attenuation of protein synthesis via eEF2 inactivation may be the mechanism of cardioprotection by AMPK.

Clinical significance of plasma endothelin-1 level after bosentan administration in pulmonary arterial hypertension

BACKGROUND Endothelin (ET)-1 has been shown to play a significant pathogenic role in pulmonary arterial hypertension (PAH). However, the pathobiological significance of increased ET-1 concentration after administration of ET receptor antagonist in patients with PAH has not yet been fully examined. METHODS In 16 PAH patients, plasma ET-1 concentration was measured at 0, 1, 3, 6, and 24h after a single 62.5mg dose of bosentan, a dual ET receptor antagonist, and the peak and 24-h change in ET-1 concentration from baseline were examined. The severity of PAH was evaluated by hemodynamic parameters, 6-min walk distance, New York Heart Association (NYHA) functional class, and brain natriuretic peptide (BNP). RESULTS Plasma ET-1 concentration significantly increased from 1.93+/-0.12 to 3.36+/-0.18 pg/ml after bosentan administration in PAH patients (p<0.01). The peak-to-baseline ratio of ET-1 concentration after bosentan administration showed a significant positive correlation with baseline ET-1 concentration (p<0.05). After 4-week bosentan administration, NYHA functional class improved in 7 patients but was not changed in 9 patients. The optimal cut-off point of % change of ET-1 concentration at 24h for discriminating the two groups was 30%. According to this cut-off point, patients were divided into the higher (n=7) and the lower (n=9) groups. NYHA functional class did not change in the lower group, but significantly improved (p<0.01) in the higher group after 4-week bosentan administration. In addition, plasma BNP levels significantly decreased from baseline in the higher group compared with those in the lower group after 12-week bosentan administration (-44+/-11% vs. 7+/-20%, p<0.05). CONCLUSIONS Although the population in this study is small and heterogeneous, measurement of plasma ET-1 concentration after bosentan administration might predict the responsiveness to bosentan treatment, and be useful in the determination of effective therapy in treatment of PAH patients.

The Frequency of Fish-Eating Could Negatively Associate with Visceral Adiposity in Those Who Eat Moderately

Visceral fat accumulation is regarded as one of the major phenotypes of metabolic syndrome. There have not been enough data on the relationship between the fish-eating habit and visceral adiposity. A total of 94 male participants received abdominal CT for the measurement of the visceral fat area (VFA), serum sampling for the fatty acid composition and questionnaires about their life-style. We divided the participants into two groups: whether they ate their fill (group F, n=70) or they ate in moderation (group M, n=24). Stepwise multiple linear regression analyses showed that usual alcohol consumption and lower daily physical activity in group F, and infrequent fish-eating and frequent fat-rich deserts in group M were the significant positive correlates with the VFA. The serum eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio showed significant correlation with the frequency of fish-eating in both groups. Interestingly, in group M, the serum EPA/AA ratio negatively correlated with the VFA, while it failed in group F. In conclusion, the present data suggest that the fish-eating habit might negatively associate with visceral fat accumulation only in those who are moderate in eating in the general population.

Great Saphenous Vein Flow Pattern as a Simple Ultrasonographic Sign of Early Recanalization of Deep Vein Thrombosis: A Case Series Report

We retrospectively examined patients with ultrasonographically occlusive acute proximal deep vein thrombosis (DVT). All patients were categorized into two groups on the basis of whether great saphenous vein (GSV) flow toward the common femoral vein was detected (flow [+]; n=10) or undetected (flow [−]; n=10). We investigated the relationship between the GSV flow pattern and DVT recanalization. Thrombus recanalization, which is defined as diameter reduction to lower than 40% of the vessel diameter, was confirmed in seven of the flow (+), and none of the flow (−). This study proposes that the GSV flow pattern may be a simple marker for the recanalization of proximal occlusive DVT.

Impact of plaque characteristics on myocardial tissue reperfusion in acute myocardial infarction

Background: The urinary excretion of 8.iso-prostaglandin F2alpha (E-iso-PGFPalpha), a marker for in viva oxidant stress, is increased during repelfusion in acute myocardlal infarction (AMI). Interestingly. 8-iso-PGF2alpha is also a vasoconstrictor, a platelet activator, and a regulator of leukocyte-endothelial interaction. The generation of 8.isoPGFPalpha from the AMI heart, thereby may contribute to poor microvascular blood flow through neutrophil plugging and vasoconstriction. No resolution of ST segment elevation despite patent epicardial coronary artery may reflect poor microvascular reflow. Hence we hypothesized that enhanced oxidant stress after reperiusion is associated with persistent ST elevation despite patent infarct-related artery (IRA). Methods: Twenty-six patients with successfully reperfused AMI by direct angioplasty were studied. Urinary 8-iso-PGFPalpha excretions were measured in the spot samples before repetiusion. the collection of the first 6 hours after it, and the spot samples in the chronic phase. The degree of enhanced oxidant stress following reperfusion was evaluated with delta urinary 8-iso-PGF2alpha defined as subtraction of its urinary excretion in the chronic phase from that in the O-6 hours. The patients were divrded into two groups based on delta urinary 8.lso-PGFPalph, i.e. patients with enhanced oxidant stress after reperfusion and patients without it; a cut-off point of delta ““nary 8-iso-PGFPalpha was 339pg/mg creatinine (median). Results: Incomplete ST resolution (<70%) despite patent IRA was more frequently observed in patients with enhanced oxidant stress than those without it (85% vs. 38%. p=O.O2). The incidences of pericardlal effusion (PE) and congestive heart failure (CHF) were higher in patients with enhanced oxidant stress than those without it (PE, 48% vs. 0% p=O.O07; CHF, 46% vs. O%, p=O.O07). Conclusion: Enhanced oxidant stress following repeifus~on is associated with absence of ST resolution despite patent epicardial coronary artery and in-hospital complications.