Tomoyuki Hamaguchi

Circulating interleukin-6 family cytokines and their receptors in patients with congestive heart failure.

Abstractgp130 is a common signal-transducing receptor subunit for the interleukin (IL)-6 cytokine family. Studies in genetically engineered animal models have demonstrated a critical role for the gp130-dependent cardiomyocyte survival pathway in the transition to heart failure. In the present study, we examined plasma levels of the IL-6 family of cytokines and the soluble form of their receptors in patients with congestive heart failure (CHF). Circulating levels of the IL-6 family of cytokines, soluble IL-6 receptor (sIL-6R), and soluble gp130 (sgp130) were examined in 48 patients with various degrees of CHF, including dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), and valvular cardiomyopathy (VCM). Circulating levels of IL-6, leukemia inhibitory factor (LIF), and sgp130 significantly increased in association with the severity of CHF. No significant difference was observed in the circulating levels of sIL-6R and IL-11 among these patients. Interestingly, DCM patients showed higher circulating sgp130 levels than patients with ICM or VCM. Our findings suggest that gp130 expression in the heart is likely to be dynamic, and that the IL-6 family of cytokines and their common receptor gp130 participates in the pathogenesis of CHF, especially in DCM.

Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump

An anticancer drug, doxorubicin, and a naturally occurring beta-amino acid, taurine, exert opposing actions on myocardial calcium content and lipid peroxidation. Thus, we tested the hypothesis that the two agents may interact to modify cardiac calcium metabolism and indices of lipid peroxidation. Cardiac taurine levels were reduced by half in rats given tap water containing a beta-amino transport inhibitor, beta-alanine. Taurine deficiency was associated with an increased susceptibility of the heart to doxorubicin-mediated calcium accumulation, a phenomenon commonly associated with doxorubicin cardiotoxicity. Taurine deficiency also predisposed the heart to enhanced formation of malondialdehyde caused by doxorubicin administration. While increases in malondialdehyde levels are often associated with lipid peroxidation, the failure of doxorubicin to cause changes in oxidized glutathione content makes peroxidative mechanisms a less likely explanation for the potentiation of doxorubicin-mediated myocardial calcium accumulation in taurine-deficient rats. A more likely possibility is the interaction between taurine deficiency and doxorubicin to inhibit the sarcolemmal calcium pump. The data also suggest that the interaction between doxorubicin and taurine deficiency does not involve alterations in the pharmacokinetics of doxorubicin or the cardiotoxic metabolite, doxorubicinol. It is concluded that reduction in sarcolemmal calcium pump activity by taurine deficiency may contribute to myocardial calcium accumulation in hearts whose calcium homeostasis has been compromised by doxorubicin.

Calcium Overload-Induced Myocardial Damage Caused by Isoproterenol and by Adriamycin: Possible Role of Taurine in its Prevention

Calcium ion (Ca2+) is essential for excitation-contraction coupling and for maintenance of cell integrity in the myocardium. On the other hand, it is clear that cytosolic Ca2+ loading may be the first event leading to cell death in certain forms of myocytic injury, such as Ca2+ paradox and isoproterenol (ISO) toxicity. The Ca2+ overload injury is characterized by an exhaustion of tissue high-energy phosphate, massive release of enzymes and extensive ultrastructural damage, as well as excessive influx of Ca2+ into the myocardial cells.

Protective effect of taurine against doxorubicin-induced cardiotoxicity in perfused chick hearts

The ability of taurine to protect the isolated heart against doxorubicin cardiotoxicity was examined. Chick hearts perfused for 20 min with medium containing 17 microM doxorubicin exhibited a decrease in contractility, an increase in resting tension and a dramatic depletion in tissue high energy phosphate content. Addition of 20 mM taurine to the perfusate attenuated the increase in resting tension and the decrease in myocardial adenosine triphosphate content induced by doxorubicin. The present study confirms our previous in vivo observations that taurine partially prevents doxorubicin-induced cardiotoxicity.

Cellular oncogene expression in the idiopathic cardiomyopathic hamster heart during the growing process

The expression of various proto-oncogenes was evaluated in the Syrian hamster with hereditary idiopathic cardiomyopathy. mRNA from the heart and aorta of controls (BIO-RB) and cardiomyopathic hamsters (UM-X7.1 strain, BIO 14.6 line) was tested using RNA hybridization techniques. Of the 19 different v-oncogene probes used in the study, only the v-myc probe revealed a substantially greater expression of oncogene in the 30th day of cardiomyopathic hamster heart than in control hamster heart. The amplified expression of c-myc was also observed in the heart of 1-year-old, but not of 7-day-old cardiomyopathic hamster. Overexpression of c-myc, otherwise associated with the regulation of cell differentiation or rapid growth, may relate to the pathological state or pathogenesis of the hereditary cardiomyopathy.

The Interleukin-6 Family of Cytokines and their Receptors in Patients with Congestive Heart Failure

gp130 is a signal-transducing protein of the interleukin (IL)-6 family of cytokines, which includes IL-6, IL-II, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1). It is widely expressed in various organs, including the heart.1 In cardiac myocytes, gp130 stimulation results in the activation of downstream signaling pathways, including the Janus kinase (JAK) / signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3 kinase (PI3K) pathway.2,3 Pathophysiologically, the gp130/STAT pathway is activated in cardiac myocytes through the autocrine/paracrine system of the IL-6 family of cytokines, including LIF and CT-1, in response to mechanical stretch, hypoxia and stimulation by neurohumoral factors.4,5