Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy.

-Cardiotrophin-1, an interleukin-6-related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1-induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1-stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1-induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein-coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1-induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein-coupled and cytokine receptors.

Arginine vasopressin increases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor.

Arginine vasopressin (AVP) is known to contribute significantly to the pathogenesis of congestive heart failure and hypertension. However, little is known about its effect on the myocardium. The present study was conducted to determine whether AVP directly increases the rate of protein synthesis in isolated, perfused rat heart, and, if so, the mechanism involved. Elevation of the aortic pressure from 60 to 120 mmHg in perfused rat heart accelerated the rate of protein synthesis which was associated with increases in cAMP levels and Ca2+ uptake. AVP (100 microM) increased Ca2+ uptake and accelerated the rate of protein synthesis without a change in cAMP concentration. The latter events were inhibited by OPC-21268 (100 microM), a selective V1 receptor antagonist, or amiloride (100 microM), an inhibitor of the Na+/H+ exchange system. However, increases in cAMP concentrations, Ca2+ uptake, and rates of protein synthesis associated with the elevated aortic pressure were not inhibited by amiloride. Thus, AVP directly increased the rate of protein synthesis via the V1 receptor that is sensitive to amiloride, a mechanism that differs from the cAMP-dependent mechanism that is responsible for the cardiac hypertrophy induced by pressure overload.

Pressure-induced expression of heat shock protein 70 mRNA in adult rat heart is coupled both to protein kinase A-dependent and protein kinase C-dependent systems.

BACKGROUND: Production of heat shock protein 70 (HSP70) in the heart is induced by hemodynamic stress, but its intracellular signal transduction system has not been elucidated well. OBJECTIVE: To investigate the hypothesis that protein kinase A (PKA)-dependent and protein kinase C (PKC)dependent systems are involved in the pressure-induced expression of HSP70 mRNA in perfused adult rat heart METHODS: Isolated tetrodotoxin-arrested Sprague-Dawley rat hearts were perfused as Langendorff preparations at a constant aortic pressure of 60 mmHg. Aortic pressure in rats of the pressure-overloaded group was elevated from 60 to 120 mmHg for 2-120 min. cAMP contents and rates of synthesis of protein were measured by radioimmunoassay and the incorporation of [14C]-phenylalanine into total heart protein, respectively. Expression of HSP70 mRNA was determined by Northern blot analysis. RESULTS: Elevation of aortic pressure significantly increased cAMP content after 2 min of perfusion (by 41%), significantly increased rates of synthesis of protein during the second hour of perfusion (by 41%), and induced expression of HSP70 mRNA maximally after 60 min of perfusion (2.7-fold the control value). Exposure to glucagon, forskolin or 1 -methyl-3-isobutylxanthine mimicked increases in these parameters caused by elevation of aortic pressure. Administration of a selective PKA inhibitor, H-89, significantly prevented induction of increases in expression of HSP70 mRNA and rates of synthesis of protein by a high pressure overload and exposure to agents that increase cAMP content. Furthermore, administration of phorbol ester induced expression of HSP70 mRNA. Administration of a PKC inhibitor, calphostin C, significantly prevented induction of increases in expression of HSP70 mRNA by a pressure overload and by exposure to phorbol ester. CONCLUSIONS: These results suggest that the pressure-induced induction of production of HSP70 is regulated both by PKA-dependent and by PKC-dependent systems during periods of active synthesis of protein in adult rat heart.

[Relationship between severity of farmer's lung and the level of soluble interleukin 2 receptors in serum].

A 54-year-old woman was admitted to Nayoro City Hospital because of a suspicion of farmer's lung (FL). She had been working on her farm for the previous 16 years. Every April she experienced fever, coughing, and dyspnea. Fine crackles were audible over both lung fields. On admission, arterial blood gas analysis showed hypoxemia, and pulmonary-function testing revealed restrictive lung disease and a low diffusing capacity. A chest X-ray film revealed radio-opacity throughout the lower lung fields. A 67Ga scintigram showed abnormal uptake in the lungs. Examination of bronchoalveolar lavage fluid revealed an abnormally high number of lymphocytes and a high CD4/CD8 ratio in the lymphocytes. Histological examination of a specimen obtained by transbronchial lung biopsy revealed interstitial pneumonitis. A precipitation test was positive for anti-Micropolyspora faeni antibody. After admission, symptoms resolved with no treatment. FL was diagnosed from anamnesis and the results of examinations. On admission, the level of soluble interleukin 2 receptor in serum was twice the upper limit of the normal value, and it decreased over time, a long with the severity of the disease. Serial measurements of levels of this receptor are clinically important for detecting the progression of adult T cell leukemia. This case suggests that they can also be useful for evaluating the severity of FL.

Differential effects of amiloride on the basal rate and the pressure overload-induced increase in protein synthesis in perfused rat heart.

The purpose of the present study were to determine the contribution of Na+/H+ exchange to pressure overload-induced cardiac hypertrophy and to examine its potential interaction with cAMP-dependent signaling pathway. Isolated rat hearts were perfused as Langendorff preparations with aortic pressure of 60 mmHg. In pressure overload group, aortic pressure was increased to 120 mmHg. cAMP contents in the heart perfused at 2 min were examined by RIA. Rates of protein synthesis were examined by 14C-phenylalanine incorporation into myocardial protein during the second hour of perfusion. Expression of c-fos mRNA in the heart perfused at 1 hour was analyzed by Northern blotting. Elevation of aortic pressure from 60 mmHg to 120 mmHg in perfused rat hearts increased cAMP contents from 4.89 +/- 0.09 to 6.30 +/- 0.28 pmol/mg protein and accelerated rates of protein synthesis from 644 +/- 13 to 860 +/- 49 mmol Phe/g dry heart/hr. Expression of c-fos mRNA was induced by elevated aortic pressure. Amiloride, an inhibitor of Na+/H+ exchange, decreased rates of protein synthesis in a concentration-dependent manner (12.5, 25, 50, 100 microM) but did not change cAMP content (5.25 +/- 0.11 pmol/mg protein) or expression of c-fos mRNA. Furthermore, amiloride did not prevent the increases in cAMP (6.99 +/- 0.34 pmol/mg protein), protein synthesis rates (476 +/- 18 to 689 +/- 31 nmolPhe/g dry heart/hr) and expressions of c-fos mRNA that were induced by elevation of aortic pressure. These results indicate that amiloride, an inhibitor of Na+/H+ exchange system, while influencing rates of protein synthesis, does not play an important role in pressure overload-induced cardiac hypertrophy. The mechanism by which amiloride influences cardiac protein synthesis is independent of the cAMP-dependent mechanism by which pressure overload induces cardiac hypertrophy.

A case report of isolated levocardia without intracardiac anomalies associated with sick sinus syndrome.

A 42-year-old female with cardiomegaly showed bradycardia without syncope. Clinical data showed that she had an isolated levocardia with interruption of the inferior vena cava. Isolated levocardia was defined as a normally placed heart associated with situs ambiguus of other viscera. She did not have intracardiac anomalies. Isolated levocardia without intracardiac anomalies, as in this case, has only been reported in 13 other cases. Isolated levocardia is often accompanied by severe complex intracardiac anomalies and, therefore, most of the patients have a short life span. Situs ambiguus, especially left isomerism, is frequently associated with deteriorated sinus node function, and an interruption of the inferior vena cava may also be an indication of this phenomenon. Therefore, the patient's sinus node function was examined using an electrophysiological study and a 24-hour ambulatory electrocardiogram. Sick sinus syndrome was finally confirmed.

Hemoglobin Kansas found in a patient with polycythemia.

A 62-year-old woman, long suspected of having heart disease, was admitted to our hospital for thorough examination. Her hemoglobin level was 17.7 g/dl and her 2.3-DPG level was 8.90 microM/ml RBC. The patient proved to have polycythemia, hemoglobin Kansas, and diabetes mellitus. To our knowledge, this is the third case of hemoglobin Kansas in the world.

[Case report of angiomyolipoma of the posterior upper mediastinum].

A case of posterior upper mediastinal angiomyolipoma is reported. The patient was an asymptomatic 63-year-old female, in whom an abnormal shadow was detected on chest x-ray at medical examination. On computed tomogram, the mass was located in the right paravertebral upper mediastinum, and its density had a CT-number of 12. It had high MRI intensity. Since there remained a possibility of malignancy, thoracotomy was carried out. The resected tumor was soft in consistency and the size was 20 x 23 x 37 mm. Histological examination showed that the mass was composed of fatty tissue, smooth muscle, and vascular tissue. Therefore, the tumor was diagnosed as angiomyolipoma. Although angiomyolipomas are often found in the kidney, those in the mediastinum are very rare and there have been only 2 cases reported in the literature. We consider that angiomyolipoma is rare, but important in the differential diagnosis of mediastinal tumors.

[Minocycline-induced pneumonia and pleurisy--a case report].

A 24-year-old woman had been treated with minocycline (MINO) for acute upper airway infection. Two days after the start of MINO therapy, she developed fever, cough, dyspnea, and bloody sputum. Her chest X-ray film revealed bilateral pleural effusions and butterfly shadow, and chest computed tomography revealed markedly increased density of pulmonary tissue in the central lung fields. Arterial blood gas analysis demonstrated severe hypoxemia. The characteristics of the pleural effusion were exudative. Based on the history of her illness and the chest X-ray findings, in addition to the laboratory findings of leukocytosis with eosinophilia and increased serum IgE, drug-induced pneumonia was suspected. Once the treatment with MINO was discontinued, her symptoms, laboratory data, and chest X-ray findings improved rapidly. Microscopic examination of a transbronchial lung biopsy specimen showed increased alveolar septal thickness with formation of Masson's bodies. Although the result of a lymphocyte stimulation test was negative for MINO, the skin test was positive for immediate response. Because of her clinical course, the possibility of induction by other drugs was excluded. This patient was therefore diagnosed to have MINO-induced pneumonia. To date, ten cases of MINO-induced pneumonia have been reported, but no previous case was associated with pleurisy.

[Effects of denopamine on hemodynamics and blood gases in secondary pulmonary hypertension].

The acute hemodynamic and blood gas changes caused by denopamine (2 micrograms/kg/min, d.i.) were investigated in 13 patients with chronic respiratory failure and secondary pulmonary hypertension. Denopamine significantly reduced mean pulmonary arterial pressure from 25 +/- 7 to 23 +/- 7 mmHg (p less than 0.05), and pulmonary vascular resistance from 314 +/- 166 to 276 +/- 168 dyne/sec/cm-5 (p less than 0.05), while mean systemic arterial pressure and systemic vascular resistance showed no significant change. Pulmonary-systemic vascular resistance ratio was reduced significantly from 0.22 +/- 0.09 to 0.18 +/- 0.09 (p less than 0.05). These findings suggest that denopamine has more marked effects on the pulmonary artery than on systemic arteries. Arterial oxygen tension (PaO2) increased significantly from 59.0 +/- 8.1 to 62.5 +/- 10.5 Torr (p less than 0.01), and arterial carbon dioxide tension (PaCO2) decreased significantly from 49.1 +/- 6.8 to 44.6 +/- 7.0 Torr (p less than 0.01) by denopamine. Mixed venous oxygen tension (PvO2), which is an indicator of tissue oxygenation, increased significantly from 33.3 +/- 3.5 to 34.4 +/- 3.3 Torr (p less than 0.05). We conclude that denopamine is thought to be useful for the improvement of hemodynamics and tissue oxygenation in patients with secondary pulmonary hypertension. However, further long-term studies are necessary to establish its therapeutic efficacy.

[Acute and chronic effects of vasodilators in a case of chronic recurrent pulmonary embolism].

A 65-year-old man was admitted to our hospital because of shortness of breath on exertion. As the results of examinations including pulmonary angiography, pulmonary perfusion scan and pulmonary ventilation scan, we diagnosed the case as chronic recurrent pulmonary embolism. Although the patient received thrombolytic therapy by a tissue plasminogen activator (t-PA), there was no noticeable improvement. However, oxygen and vasodilator therapy had marked effective on the hemodynamics. In chronic pulmonary embolism, vasodilators are generally not considered to be effective for improvement of hemodynamics. However, if the acute effects of vasodilators were confirmed, we should try to administer them while paying attention to possible adverse effects.