Disease relevance of MCTP1

• Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by pulmonary vascular remodeling, pulmonary hypertension, and compensatory right heart hypertrophy [1].
• When low, intravenous doses of MCTP are given to rats, a delay of several days occurs before lung injury and pulmonary hypertension become apparent [2].
• These findings suggest that molecular events underlying MCTP toxicity are initiated at the plasma membrane or readily accessible subcellular regions including the cytosol and membranes of the endoplasmic reticulum and mitochondria [3].

High impact information on MCTP1

• Surprisingly, we found that none of the three MCTP1 C2 domains interacted with negatively charged or neutral phospholipids in the presence or absence of Ca2+ [4].
• All MCTP C2 domains except for the second C2 domain of MCTP2 include a perfect Ca2+/phospholipid-binding consensus sequence [4].
• Nevertheless, megalocytotic MCTP-treated cells showed reduced entry into mitosis upon stimulation with 2-methoxyestradiol (2-ME), reduced 2-ME-induced Golgi fragmentation, and a slowing of Golgi reassembly after nocodazole-induced fragmentation [5].
• Largely based upon data from endothelial cells, we proposed earlier that a disruption of the trafficking and mitosis-sensor functions of the Golgi (the "Golgi blockade" hypothesis) may represent the subcellular mechanism leading to MCTP-induced megalocytosis [6].
• In cultured endothelial cells, a single exposure to the pyrrolic derivative of monocrotaline (MCTP) results in large cells with enlarged endoplasmic reticulum (ER) and Golgi and increased vacuoles [6].

Chemical compound and disease context of MCTP1

• Monocrotaline pyrrole (MCTP) is a pyrrolizidine alkaloid that causes pulmonary vascular injury and pulmonary hypertension in rats [7].

Biological context of MCTP1

• These data suggest that a disruption of the trafficking and mitosis sensor functions of the Golgi may represent the subcellular mechanism leading to MCTP-induced megalocytosis ("the Golgi blockade hypothesis") [5].
• The response of HPAEC to MCTP was compared with that of adriamycin and nocodazole, agents known to cause cell cycle alterations [8].
• A stable analog of thromboxane A2(TxA2) caused a greater increase in right ventricular pressure in MCTP-treated rats compared to controls, and lungs isolated from MCTP-treated rats produced more TxB2 than those of controls [2].
• Phosphorylation of several D-glucose derivatives has been achieved using inorganic monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution [9].

Anatomical context of MCTP1

• To better characterize the cell cycle regulatory mechanisms of this process as well as determine whether this process would occur in cells of human origin, we treated human pulmonary artery endothelial cell (HPAEC) cultures with MCTP and determined, by flow cytometry, the expression of cyclin B1 and p53 in conjunction with DNA content [8].
• Adoptive transfer of lymphocytes did not decrease the onset time of the injury or increase the severity of lesions due to MCTP in the recipients [7].
• Moderate depletion of blood platelets around the time of the onset of lung injury lessens the subsequent development of right ventricular enlargement, suggesting a reduction in the pulmonary hypertensive response to MCTP [2].
• These results indicate that MCTP causes a direct, dose-dependent injury to pulmonary vascular endothelium in culture that is delayed and progressive and suggest a mechanism by which MCT may act in vivo to cause lung injury and pulmonary hypertension [10].
• A single application of MCTP to confluent monolayers of cultured endothelium from bovine pulmonary artery results in release of lactate dehydrogenase, some cell detachment from the growth surface and markedly altered morphology of remaining viable cells [10].

Associations of MCTP1 with chemical compounds

• MCT is bioactivated by the liver to a reactive, electrophilic pyrrole (MCTP) that travels via the circulation to the lung, where injury results [2].
• Neither ALS nor CyA completely protected rats from the injury due to MCTP [7].
• However, administration of drugs that either inhibited thromboxane synthesis or antagonized the effects of thromboxane did not afford protection from MCTP in vivo [2].
• Serotonin (5HT), another vasoactive mediator released by platelets, caused an exaggerated vasoconstrictor response in isolated lungs from rats treated with MCTP [2].
• For the first time, MCTP adducts were observed on proteins not known to contain cysteine residues [3].

Analytical, diagnostic and therapeutic context of MCTP1

• Thus, the MCTP-treated rat is a good animal model for this disease [7].

References