Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Stress is increasingly associated with heart disease. Glucocorticoids are primary stress hormones, yet their direct role in the heart is poorly understood. Mice lacking the glucocorticoid receptor specifically in cardiomyocytes die prematurely from heart failure. The deficiency in glucocorticoid signaling leads to the aberrant regulation of a large cohort of genes strongly associated with both cardiovascular and inflammatory disease processes. These findings reveal an obligate role for cardiomyocyte glucocorticoid receptors in maintaining normal heart function and define a paradigm for stress in cardiovascular disease

Complete achromatopsia associated with skeletal anomalies: A new autosomal recessive syndrome

Achromatopsia or rod monochromatism is the complete absence of color discrimination, with an estimated frequency of 1 in 100,000. To date the McKusick Catalogue includes more than 10 entities related to Achromatopsia. This paper describes four Mexican sibs with a stationary rod monochromatism, associated with long fingers and toes, hypothenar and thenar hypoplasia and pes planus, suggesting a new genetic entity probably inherited in an autosomal recessive mode

Novel serum biomarkers for erythropoietin use in humans: a proteomic approach

Erythropoietin (Epo) is produced primarily in the kidneys upon low blood oxygen availability and stimulates erythropoiesis in the bone marrow. Recombinant human Epo (rHuEpo), a drug developed to increase arterial oxygen content in patients, is also illicitly used by athletes to improve their endurance performance. Therefore, a robust and sensitive test to detect its abuse is needed. The aim of the present study was to investigate potential human serum biomarkers of Epo abuse employing a proteomic approach. Eight healthy male subjects were injected subcutaneously with rHuEpo (5,000 IU) every second day for a 16-day period. Serum was collected before starting the treatment regime and again at days 8 and 16 during the treatment period. Samples were homogenized and proteins separated by two-dimensional gel electrophoresis (2DE). Spots that changed significantly in response to rHuEpo treatment were identified by mass spectrometry. Both the number of reticulocytes and erythrocytes increased throughout the study, leading to a significant increase in hematocrit and hemoglobin content. In addition, transferrin levels increased but the percentage of iron bound to transferrin and ferritin levels decreased. Out of 97 serum proteins, seven were found to decrease significantly at day 16 compared with pre-Epo administration, and were identified as four isoforms of haptoglobin, two isoforms of transferrin, and a mixture of hemopexin and albumin. In support, total serum haptoglobin levels were found to be significantly decreased at both days 8 and 16. Thus a 2DE proteomic approach for discovery of novel markers of Epo action appears feasible

Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice

Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction and died prematurely from heart failure. In contrast, the cardioMRKO mice exhibited normal heart morphology and function. Despite the presence of myocardial stress, the cardioGRMRdKO mice were resistant to the cardiac remodeling, left ventricular dysfunction, and early death observed in the cardioGRKO mice. Gene expression analysis revealed the loss of gene changes associated with impaired Ca(2+) handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Reexpression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure. These findings reveal a critical role for balanced cardiomyocyte GR and MR stress signaling in cardiovascular health. Therapies that shift stress signaling in the heart to favor more GR and less MR activity may provide an improved approach for treating heart disease

<Articles>The Turning Point in the Role of the Todaiji Daikanjin

本稿では東大寺大勧進円照の分析を通じて、大勧進と造営料国を取り巻く状況の変容を明らかにした。大勧進円照が登場する歴史的前提には、別当定親による造営料国の知行という事態があった。これにより寺僧等は造営料国の富に注目し始めていく。そうした中で大勧進に就任した円照は、という原則を転換し、正税等を恒常的に修造用途に充当する体制を作ったほか、さらにそれを寺家用途・寺僧得分にも振り分ける流れを基礎付けた。しかし、円照のこうした人法に対する視線は別当定親との有縁関係に規定される側面を有していた。つまり、円照の画期性は定親との有縁関係という特有の条件から現れたといえるのである。造営料国の富が寺内に還元されていく動きは十三世紀後半には定着した。だが、それによりかえって寺内には深刻な対立が醸成されていった。「関東止住名誉僧」の大勧進はそのような問題の反動から要請された存在なのである。This article elucidates the changes in the circumstances of the zoeiryogoku 造営料国 (provinces supporting building and maintenance) and the Daikanjin 大勧進 (the officer in charge of "the great campaign" to support the temple) through an analysis of role of the Todaiji 東大寺 Daikanjin Ensho. 円照 An historical prerequisite for Ensho's appearance as Daikanjin was the fact of the abbot Joshin's 定親 control of the zoeiryogoku, which was the impetus for the temple community to first become conscious of the wealth that might be obtained from the supporting provinces. Appointed to the office of Daikanjin, Ensho bore these expectations of the temple (jike 寺家) and he altered the principle that returns from the supporting provinces were to be used for temple operations and building, and instead not only built up a system in which the annual "rice" tax would be constantly allotted to the cost of repairs, but also began the practice of distributing it to the temple and individual monks themselves. If compared with the prior operation of the Daikanjin, these actions can be termed a major turning point in its basic character. Nevertheless, Ensho's policy of supporting ninpo 人法 of Todaiji contains aspects that are undoubtedly related to the abbot Joshin. In other words, the groundbreaking quality of the Daikanjin Ensho appeared as a result of their unique connection with Joshin. The trend of having the wealth of the supporting provinces returned directly to the temple became standard practice in the latter half of the 13th century. However, profound splits among the monks began to brew within the temple as a result. The appearance of famous monks who lived in Kanto 関東止住名誉僧 as Daikanjin was a result of the discord and chaos within the temple

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Heart failure is a leading cause of death in humans, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones, but their direct role in cardiovascular health and disease is poorly understood. To determine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of the glucocorticoid receptor (GR). These mice are born at the expected Mendelian ratio, but die prematurely from spontaneous cardiovascular disease. By 3 mo of age, mice deficient in cardiomyocyte GR display a marked reduction in left ventricular systolic function, as evidenced by decreases in ejection fraction and fractional shortening. Heart weight and left ventricular mass are elevated, and histology revealed cardiac hypertrophy without fibrosis. Removal of endogenous glucocorticoids and mineralocorticoids neither augmented nor lessened the hypertrophic response. Global gene expression analysis of knockout hearts before pathology onset revealed aberrant regulation of a large cohort of genes associated with cardiovascular disease as well as unique disease genes associated with inflammatory processes. Genes important for maintaining cardiac contractility, repressing cardiac hypertrophy, promoting cardiomyocyte survival, and inhibiting inflammation had decreased expression in the GR-deficient hearts. These findings demonstrate that a deficiency in cardiomyocyte glucocorticoid signaling leads to spontaneous cardiac hypertrophy, heart failure, and death, revealing an obligate role for GR in maintaining normal cardiovascular function. Moreover, our findings suggest that selective activation of cardiomyocyte GR may represent an approach for the prevention of heart disease