Hepatocyte growth factor (HGF) and its receptor, c-Met, play pivotal roles in the nervous system during development and in disease states. However, the physiological roles of HGF in the adult brain are not well understood. In the present study, to assess its role in learning and memory function, we used transgenic mice that overexpress HGF in a neuron-specific manner (HGF-Tg) to deliver HGF into the brain without injury. HGF-Tg mice displayed increased alternation rates in the Y-maze test compared with age-matched wild-type (WT) controls. In the Morris water maze (MWM) test, HGF-Tg mice took less time to find the platform on the first day, whereas the latency to escape to the hidden platform was decreased over training days compared with WT mice. A transfer test revealed that the incidence of arrival at the exact location of the platform was higher for HGF-Tg mice compared with WT mice. These results demonstrate that overexpression of HGF leads to an enhancement of both short- and long-term memory. Western blot analyses revealed that the levels of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, but not NR1, were increased in the hippocampus of HGF-Tg mice compared with WT controls, suggesting that an upregulation of NR2A and NR2B could represent one mechanism by which HGF enhances learning and memory performance. These results demonstrate that modulation of learning and memory performance is an important physiological function of HGF that contributes to normal CNS plasticity, and we propose HGF as a novel regulator of higher brain functions.
Objective Low serum cholesterol is associated with a poor prognosis in patients with chronic heart failure (CHF). However, the relationships between the serum cholesterol level, production of monocyte proinflammatory cytokines and long-term prognosis in CHF patients remain unclear. Methods A total of 95 CHF patients who had not been treated with statins and had a mean left ventricular ejection fraction of 26.0±6.0% were examined. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α and interleukin (IL)-6 was measured and expressed as the mean ± SD (pg/mL/10 6 PBMCs). Results The production of monocyte TNF-α and IL-6 was found to be significantly and negatively associated with the serum low-density lipoprotein (LDL)-cholesterol level (TNF-α: r=-0.515, p<0.001, IL-6: r= -0.419, p<0.001). During a median follow-up of 66.0 months, 49 patients developed cardiac events, including 21 cardiac deaths and 28 readmissions for worsening CHF. A multivariate Cox hazard analysis showed that a monocyte TNF-α level of ! 4.9 pg/mL/10 6 PBMCs [hazard ratio (HR) 187.38, 95% confidence interval (CI) 7. 92-4,434.94, p=0.001] and LDL-cholesterol level of <120 mg/dL (HR 9.41, 95% CI 1.02-86.66, p=0.048) were independently associated with the incidence of cardiac events. Conclusion Low LDL-cholesterol and the upregulation of monocyte proinflammatory cytokine production are both significantly and independently associated with poor outcomes in CHF patients.
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