These results indicate that the protective effect of dehydroepiandrosterone against hypoxic pulmonary hypertension may involve upregulation of pulmonary artery soluble guanylate cyclase protein expression and augmented pulmonary artery vasodilator responsiveness to nitric oxide.

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Genes expressed with day/night rhythms in the mouse liver were searched for by microarray analysis using an in-house array harboring mouse liver cDNAs. The rhythmic expression with a single peak and trough level was confirmed by RNA blot analysis for 3␤-Hsd and Gabarapl1 genes exhibiting a peak in the light phase and Spot14, Hspa8, Hspa5, and Hsp84-1 genes showing a peak in the dark phase. On the other hand, mRNA levels for all of the three fibrinogen subunits, A␣, B␤ and ␥, exhibited two peaks each in the light and dark phases in a synchronized manner. This two-peaked rhythmic pattern of fibrinogen genes as well as the single peaktrough pattern of other genes was diminished or almost completely lost in the liver of Clock mutant mice, suggesting that the two-peaked expression is also under the control of oscillation-generating genes. In constant darkness, the first peak of the expression rhythm of fibrinogen genes was almost intact, but the second peak disappeared. Therefore, although the first peak in the subjective day is a component of the innate circadian rhythm, the second peak seems to require light stimuli. Fasting in constant darkness caused shifts of time phases of the circadian rhythms. Protein levels of the fibrinogen subunits in whole blood also exhibited circadian rhythms. In the mouse and human loci of the fibrinogen gene cluster, a number of sequence elements resembling circadian transcription factor-binding sites were found. The fibrinogen gene locus provides a unique system for the study of two-peaked day/night rhythms of gene expression in a synchronized form.In mammals, intracellular oscillation generators for circadian rhythms reside in various peripheral organs such as liver as well as in the central pacemaker, the suprachiasmatic nucleus (SCN) 1 of the hypothalamus (1, 2). The SCN and peripheral tissues seem to share common molecular mechanisms for generating the circadian oscillation. The widely accepted mechanism is autoregulatory feedback inhibition of period (Per) and cryptochrome (Cry) genes by their own protein products in antagonism with the positive transcription factor of the CLOCK-BMAL1 heterodimer (3-8).The time phase of the SCN oscillator is adjusted by light stimuli everyday in the light-dark condition (1, 2). The SCN then controls or affects the oscillators of peripheral cells in both relatively direct and indirect manners. The liver provides a well characterized example of these regulations. Although oscillation generators of liver cells are under the circadian control of glucocorticoids (9, 10), presumably through the hypothalamus-hypophysis-adrenal axis, time phases of the liver oscillators are more profoundly affected by feeding time (11-13). Artificial diurnal feeding of nocturnal rodents can completely uncouple the oscillation phase of the liver from that of the SCN. Seemingly, the SCN regulates the liver oscillators indirectly by controlling the sleep-awakeness phase that in turn determines the feeding time under the natural condition.Recently, hundreds of genes exhibit...

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