Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II.

Bone morphogenetic proteins (BMPs) are critically involved in early development and cell differentiation. In humans, dysfunction of the bone morphogenetic protein type II receptor (BMPR-II) is associated with pulmonary arterial hypertension (PAH) and neoplasia. The ability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma and primary effusion lymphoma, to down-regulate cell surface receptor expression is well documented. Here we show that KSHV infection reduces cell surface BMPR-II. We propose that this occurs through the expression of the viral lytic gene, K5, a ubiquitin E3 ligase. Ectopic expression of K5 leads to BMPR-II ubiquitination and lysosomal degradation with a consequent decrease in BMP signaling. The down-regulation by K5 is dependent on both its RING domain and a membrane-proximal lysine in the cytoplasmic domain of BMPR-II. We demonstrate that expression of BMPR-II protein is constitutively regulated by lysosomal degradation in vascular cells and provide preliminary evidence for the involvement of the mammalian E3 ligase, Itch, in the constitutive degradation of BMPR-II. Disruption of BMP signaling may therefore play a role in the pathobiology of diseases caused by KSHV infection, as well as KSHV-associated tumorigenesis and vascular disease

Vasorelaxant effects of SCA40 (a phosphodiesterase III inhibitor) in pulmonary vascular preparations in rats

1. The novel phosphodiesterase (PDE) inhibitor SCA40 (6-bromo-8(methylamino)imidazo[1,2-a]pyrazine-2- carbonitrile) was examined for its vasorelaxant activity on isolated pulmonary vascular preparations from rats. 2. SCA40 relaxed ring preparations of main and intralobar pulmonary artery precontracted submaximally with either phenyl ephrine or U46619 (thromboxane-mimetic). Based on negative log EC values, SCA 40 was six- to 14-fold more potent than the PDE III inhibitor milrinone or the non-selective PDE inhibitor 3-isobutyl-1 methyl xanthine (IBMX). The potency of SCA 40 corresponded to its reported potency as a PDE III inhibitor. 3. In isolated perfused lungs, SCA40 reversed the vasoconstriction induced by alveolar hypoxia. It was 49-fold more potent than IBMX. 4. In main pulmonary artery the vasorelaxation induced by SCA40 was not blocked by the large-conductance calcium-activated potassium channel (BK(Ca)) inhibitors iberiotoxin (50 and 100 nmol/L) or charybdotoxin (100 and 300 nmol/L). This was in contrast to data on guinea-pig trachea, where responses to SCA40 were significantly inhibited by charybdotoxin (100 nmol/L). 5. It is concluded that opening of BK(Ca) channels does not contribute to the pulmonary vasorelaxant effects of SCA40 in main pulmonary artery and it is likely that responses reflect the PDE III inhibitory properties of the drug. 6. It is postulated that SCA 10 may be useful as a pulmonary vasodilator in disorders such as pulmonary hypertension