Inhibition of platelet function by A02131-1, a novel inhibitor of cGMP- specific phosphodiesterase, in vitro and in vivo

The effect of A02131-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl thieno (3,2-c)pyrazole], a cGMP-specific phosphodiesterase (PDE) inhibitor, on platelet function was investigated. The compound was found to inhibit the aggregation of and adenosine triphosphate (ATP) release from human platelet-rich plasma and washed platelets that were induced by aggregation inducing drugs such as arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), adenosine diphosphate (ADP) and A23187, and the inhibitory effect was concentration-dependent. A02131-1 also disaggregated the performed platelet aggregates induced by these inducers. Thromboxane B2 (TXB2) formations caused by collagen, PAF, ADP, and A23187 were inhibited by A02131-1 at concentrations that did not affect the AA-induced formation of TXB2 and prostaglandin D2 (PGD2). A02131-1 suppressed both the generation of inositol 1,4,5- triphosphate (IP3) and the increase of intracellular Ca2+ concentration stimulated by these aggregation inducers. A02131-1 was shown to increase the cAMP and cGMP levels in platelets and the extent was found to be dependent on concentration as well as time. A02131-1 increased the cAMP level much more slowly than the cGMP level. Activities of adenylate cyclase, guanylate cyclase, and PDEs (type I and III) were not altered by A02131-1. However, the activity of cGMP-specific PDE (type V) was inhibited by A02131-1. The antiplatelet aggregation activity and the effect on raising cAMP level of A02131-1 were both potentiated by prostaglandin E1 (PGE1). In the mouse tail bleeding test, A02131-1 was clearly shown to be more effective than dipyridamole in prolonging the tail bleeding time of conscious mice. These data indicate that A02131-1 is a cGMP-specific PDE (type V) inhibitor in human platelets.     

Nasal chondromesenchymal hamartoma causing sleep-disordered breathing in an infant

Nasal chondromesenchymal hamartoma is an extremely rare neoplasm of the nasal and paranasal sinuses. We present the case of a 10-month-old boy with a huge nasal chondromesenchymal hamartoma that was complicated by sleep-disordered breathing. The mass was completely resected by image-guided endoscopic surgery and confirmed histopathologically as a chondromesenchymal hamartoma. In this report, we discuss the characteristics and treatment of this unusual tumor.     

Nutrient Stress Activates Inflammation and Reduces Glucose Metabolism by Suppressing AMP-Activated Protein Kinase in the Heart

OBJECTIVE

Heart failure is a major cause of mortality in diabetes and may be causally associated with altered metabolism. Recent reports indicate a role of inflammation in peripheral insulin resistance, but the impact of inflammation on cardiac metabolism is unknown. We investigated the effects of diet-induced obesity on cardiac inflammation and glucose metabolism in mice.

RESEARCH DESIGN AND METHODS

Male C57BL/6 mice were fed a high-fat diet (HFD) for 6 weeks, and heart samples were taken to measure insulin sensitivity, glucose metabolism, and inflammation. Heart samples were also examined following acute interleukin (IL)-6 or lipid infusion in C57BL/6 mice and in IL-6 knockout mice following an HFD.

RESULTS

Diet-induced obesity reduced cardiac glucose metabolism, GLUT, and AMP-activated protein kinase (AMPK) levels, and this was associated with increased levels of macrophages, toll-like receptor 4, suppressor of cytokine signaling 3 (SOCS3), and cytokines in heart. Acute physiological elevation of IL-6 suppressed glucose metabolism and caused insulin resistance by increasing SOCS3 and via SOCS3-mediated inhibition of insulin receptor substrate (IRS)-1 and possibly AMPK in heart. Diet-induced inflammation and defects in glucose metabolism were attenuated in IL-6 knockout mice, implicating the role of IL-6 in obesity-associated cardiac inflammation. Acute lipid infusion caused inflammation and raised local levels of macrophages, C-C motif chemokine receptor 2, SOCS3, and cytokines in heart. Lipid-induced cardiac inflammation suppressed AMPK, suggesting the role of lipid as a nutrient stress triggering inflammation.

CONCLUSIONS

Our findings that nutrient stress activates cardiac inflammation and that IL-6 suppresses myocardial glucose metabolism via inhibition of AMPK and IRS-1 underscore the important role of inflammation in the pathogenesis of diabetic heart.Type 2 diabetes is the most common metabolic disease in the world, affecting >250 million people, and cardiovascular disease is the leading cause of mortality in diabetes (1). Although the underlying mechanism by which diabetes increases cardiovascular events is unknown, perturbations in cardiac metabolism are among the earliest diabetes-induced alterations in the myocardium, preceding both functional and pathological changes, and may play a causative role in diabetic heart failure (2,3). Studies using isolated perfused-heart preparations, cultured cardiomyocytes, and positron emission tomography uniformly showed insulin resistance in human and animal models of diabetic heart (4,5). Diabetic heart is also characterized with elevated lipid oxidation with reciprocal reduction in glucose metabolism (6). Our recent study (7) found that chronic high-fat feeding impairs myocardial glucose metabolism, and this was associated with ventricular hypertrophy and cardiac dysfunction in obese mice. These findings highlight the importance of understanding the mechanism by which obesity and diabetes affect cardiac metabolism.Increasing evidence indicates the role of chronic inflammation and macrophage activation in insulin resistance (8,9). A cohort of recent studies (10–13) demonstrated increases in macrophage infiltration and cytokine expression in adipose tissue and their association with insulin resistance in obese humans and animal models. Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that is secreted by macrophages and adipocytes and is shown to cause insulin resistance by inhibiting insulin signaling, AMP-activated protein kinase (AMPK), and the glucose transport system (14,15). Interleukin (IL)-6 is another proinflammatory cytokine that is elevated in obese diabetic subjects and is shown to cause insulin resistance by activating STAT3-suppressor of cytokine signaling 3 (SOCS3) expression and inhibiting the insulin signaling pathway in liver and adipose tissue (16–18). However, the role of IL-6 in insulin resistance remains debatable largely due to its differential effects on glucose metabolism in skeletal muscle, adipose tissue, and liver (19). Despite the wealth of information on the role of inflammation in peripheral insulin resistance, the impact of inflammation on cardiac metabolism has not been previously addressed. In this article, we demonstrate that diet-induced obesity increases macrophage and cytokine levels in heart. IL-6 reduces glucose metabolism by suppressing AMPK and insulin receptor substrate (IRS)-associated insulin signaling in heart, whereas IL-6–deficient mice are protected from diet-induced alterations in glucose metabolism. The fact that acute lipid infusion increases the inflammatory response and impairs myocardial glucose metabolism, similar to the effects of high-fat feeding, suggests the role of nutrient stress in the activation of toll-like receptor (TLR) 4 signaling and inflammation in heart. Since glucose is an important source of energy for a working heart, particularly during ischemia, our findings identify an important role of inflammation in the pathogenesis of diabetic heart failure.     

Expression of a Common LQT1 Mutation in Five Apparently Unrelated Families in a Regional Inherited Arrhythmia Clinic

Expression of a Common LQT1 Mutation. Background: The Inherited Arrhythmia Clinic at the University of Western Ontario services a catchment area of 1.5 million people and follows families with inherited arrhythmia syndromes. Methods: Patients referred for evaluation of long‐QT Syndrome (LQTS) are evaluated with resting and standing ECGs, and treadmill exercise testing. Patients with findings consistent with LQTS are offered comprehensive genetic testing with screening of all first‐degree relatives of genotype‐positive patients. Results: Among 31 probands with disease‐causing LQTS mutations, 5 probands from apparently unrelated families of Irish descent were found to have an identical disease causing transmembrane mutation in KCNQ1 (Leu266Pro). Systematic screening of 33 first‐degree relatives of genotype‐positive individuals detected 15 unaffected and 18 asymptomatic affected family members. Symptoms in 6 patients occurred later in life than reported LQT1 populations (61 ± 18 years, range 44–89). In this cohort, several family members presented with cardiac arrest during acute myocardial ischemia (n = 2), sudden death, unexplained drowning, and torsade de pointes during exercise testing. There was no identifiable common relative for this cohort after pedigree construction of the previous 4–7 generations. Affected patients had mild QT prolongation at rest with dramatic QT prolongation with exercise. Conclusions: Genetic testing in this LQTS population suggests a common KCNQ1 Leu266Pro founder effect, with the descendants clustering in our geographical region even though no common relative has been identified. The observations highlight the utility of genotypic and phenotypic correlation and a specialized clinic. (J Cardiovasc Electrophysiol, Vol. 21, pp. 296–300, March 2010)     

Lack of modifying effects of genistein on disruption of the reproductive system by perinatal dietary exposure to ethinylestradiol in rats

We previously found that effects of perinatal dietary exposure to ethinylestradiol (EE) on the rat reproductive system differ depending on the diet used, with a more pronounced estrogenic impact with a regular diet that includes soy-derived proteins than with a soy-free (SF) diet. The present study was performed to examine whether genistein (GEN), a soy-derived major phytoestrogen, acts synergistically with EE. Maternal rats were fed SF diet without chemical (control) or containing 0.5-ppm EE, 0.5-ppm EE + 100-ppm GEN, 0.5-ppm EE + 1250-ppm GEN, or 1250-ppm GEN, from gestational day 15 to postnatal day (PND) 11. EE reduced serum testosterone in males at PND 3, and affected the onset of puberty of both sexes and estrous cyclicity and reproductive system in females, irrespective of co-administration of GEN. GEN alone also affected estrous cyclicity and the reproductive system in females. However, no combination effects of GEN with EE were evident, suggesting no synergism between the two.     

New quassinoids, javanicolides C and D and javanicosides B--F, from seeds of Brucea javanica

Two new quassinoids, javanicolides C and D, and five new quassinoid glucosides, javanicosides B-F, were isolated from the seeds of Brucea javanica, along with eight known quassinoids, i.e., yadanziolides A, C, D, and S, bruceins D and E, brusatol, and the aglycone of yadanzioside D, and 19 known quassinoid glucosides, i.e., yadanziosides A-G, I, and K-P, bruceosides A-C and E, and bruceantinoside A. Their structures were elucidated by analysis of spectroscopic data and chemical evidence.     

Endoxin antagonist lessens myocardial ischemia reperfusion injury

Endoxin antagonist lessens myocardial ischemia reperfusion injury@柯永胜$Department of Cardiology, Yijishan Hospital, Wannan Medical College, Wuhu, 241001 China @王德国$Department of Cardiology, Yijishan Hospital, Wannan Medical College, Wuhu, 241001 C