Tadashi Tanabe

Gene transfer therapy by either type 1 or type 2 adeno-associated virus expressing human prostaglandin I2 synthase gene is effective for treatment of pulmonary arterial hypertension.

Prostaglandin I2 (PGI2) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI2 involves continuous intravenous infusion using an indwelling catheter, which limits the patient’s quality of life and increases the risk of infection. We therefore investigated whether human PGI2 synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10% O2). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.

Overexpression of cyclooxygenase-2 stimulates amyloid β-peptide production in neuronal cells

Abstract Alzheimers disease (AD) is characterized by deposition of amyloid β-peptide (Aβ) derived from amyloid precursor protein (APP). Recent studies suggest that cyclooxygenase (COX)-2 is involved in the progress of AD. However, the mechanistic relationship between COX-2 expression and the neurodegenerative process of AD is unclear. To address this issue, we established neuroblastoma×glioma hybrid NG108-15 cells stably expressing human COX-2. The original cells are devoid of COX-2, but express a low level of COX-1. The COX-2-expressing cells showed three- to fourfold increase in COX activity and prostaglandin E 2 production. Reverse transcription-polymerase chain reaction analysis demonstrated that APP expression was increased by approximately twofold in the COX-2-expressing cells as compared with control cells. The secretion of proteolytic products of APP, Aβ and a secreted form of APP was also increased. A COX inhibitor, indomethacin, suppressed the production of the secreted form of APP and Aβ by inhibition of APP expression. These results suggest that COX-2 is involved in the formation of the amyloid plaques through the increased of Aβ in AD.

Two Types of Arachidonate 12-Lipoxygenase Demonstrated by Enzymological Immunological and Molecular Biological Studies

Each branch of the arachidonate cascade is initiated by a lipoxygenase reaction, by which a certain carbon atom of arachidonic acid is oxygenated. Several lipoxygenases have been found in mammalian tissues, and their physiological and pathological roles have been studied (1,2). Unlike cyclooxygenase and 5-lipoxygenase, which initiate the synthesis of prostaglandins and leukotrienes, general physiological functions of other mammalian lipoxygenases remain still unclarified.