Non-canonical transcriptional regulation of heme oxygenase in Aedes aegypti.

Heme oxygenase (HO) is a ubiquitous enzyme responsible for heme breakdown, which yields carbon monoxide (CO), biliverdin (BV) and ferrous ion. Here we show that the Aedes aegypti heme oxygenase gene (AeHO - AAEL008136) is expressed in different developmental stages and tissues. AeHO expression increases after a blood meal in the midgut, and its maximal transcription levels overlaps with the maximal rate of the further modified A. aegypti biglutaminyl-biliverdin (AeBV) pigment production. HO is a classical component of stress response in eukaryotic cells, being activated under oxidative stress or increased heme levels. Indeed, the final product of HO activity in the mosquito midgut, AeBV, exerts a protective antioxidant activity. AeHO, however, does not seem to be under a classical redox-sensitive transcriptional regulation, being unresponsive to heme itself, and even down regulated when insects face a pro-oxidant insult. In contrast, AeHO gene expression responds to nutrient sensing mechanisms, through the target of rapamycin (TOR) pathway. This unusual transcriptional control of AeHO, together with the antioxidant properties of AeBV, suggests that heme degradation by HO, in addition to its important role in protection of Aedes aegypti against heme exposure, also acts as a digestive feature, being an essential adaptation to blood feeding.

Heme oxygenase-1/biliverdin/carbon monoxide pathway downregulates hypernociception in rats by a mechanism dependent on cGMP/ATP-sensitive K+ channels.

OBJECTIVE AND DESIGN: To investigate the role of heme oxygenase-1 (HO-1), carbon monoxide (CO), and biliverdin (BVD) in the zymosan-induced TMJ arthritis in rats. MATERIALS AND METHODS: Mechanical threshold was assessed before and 4 h after TMJ arthritis induction in rats. Cell influx, myeloperoxidase activity, and histological changes were measured in the TMJ lavages and tissues. Trigeminal ganglion and periarticular tissues were used for HO-1, TNF-α, and IL-1ß mRNA time course expression and immunohistochemical analyses. Hemin (0.1, 0.3, or 1 mg kg-1), DMDC (0.025, 0.25, or 2.5 µmol kg-1), biliverdin (1, 3, or 10 mg kg-1), or ZnPP-IX (1, 3 or 9 mg kg-1) were injected (s.c.) 60 min before zymosan. ODQ (12.5 µmol kg-1; s.c.) or glibenclamide (10 mg kg-1; i.p.) was administered 1 h and 30 min prior to DMDC (2.5 µmol kg-1; s.c), respectively. RESULTS: Hemin (1 mg kg-1), DMDC (2.5 µmol kg-1), and BVD (10 mg kg-1) reduced hypernociception and leukocyte migration, which ZnPP (3 mg kg-1) enhanced. The effects of DMDC were counteracted by ODQ and glibenclamide. The HO-1, TNF-α, and IL-1ß mRNA expression and immunolabelling increased. CONCLUSIONS: HO-1/BVD/CO pathway activation provides anti-nociceptive and anti-inflammatory effects on the zymosan-induced TMJ hypernociception in rats.