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1.
Am J Pathol ; 163(5): 1921-8, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14578191

ABSTRACT

Elevated semicarbazide-sensitive amine oxidase (SSAO) activity has been observed in several human conditions, eg, diabetes, and it has been speculated that SSAO contributes to the development of vasculopathies associated with this disease. To investigate in vivo consequences of elevated expression of SSAO in vascular tissues, we have developed a transgenic model for overexpression of human SSAO in mice. A smooth muscle-specific promoter, smooth muscle alpha-actin promoter 8 (SMP8) was used. Transgenic expression of human SSAO in tissues with a high content of smooth muscle cells was confirmed by Northern blot analysis. Enzymatic analysis of homogenates from transgenic tissues showed elevated levels of SSAO activity compared to non-transgenic littermates. Furthermore, when plasma SSAO activity was analyzed, much higher activity was detected compared to plasma from control mice, indicating that plasma SSAO may originate from smooth muscle cells. Histopathological evaluation of aorta and renal artery from transgenic mice revealed an abnormal structure of the elastin tissue. Instead of the regularly folded elastic laminae normally found in tunica media of sacrificed mice, the elastic laminae were straight and unfolded with irregularly arranged elastic fibers, forming tangled webs, between the intercalating elastic laminae. These alterations of the elastin structures suggest that overexpression of SSAO has led to a reduced elasticity of the arteries. Moreover, the mean femoral arterial pressure of the SMP8 SSAO transgenic mice was significantly lower in comparison to non-transgenic littermates. This suggests that the transgenic mice have a defect in their ability to regulate blood pressure.


Subject(s)
Amine Oxidase (Copper-Containing)/biosynthesis , Aorta/pathology , Myocytes, Smooth Muscle/enzymology , Amine Oxidase (Copper-Containing)/blood , Amine Oxidase (Copper-Containing)/genetics , Animals , Aorta/enzymology , Aorta/ultrastructure , Arteries/pathology , Arteries/physiopathology , Blood Pressure/genetics , Blood Pressure/physiology , Blotting, Northern , Elastin/ultrastructure , Humans , Mice , Mice, Transgenic , Promoter Regions, Genetic , Up-Regulation
2.
Eur J Pharmacol ; 467(1-3): 211-8, 2003 Apr 25.
Article in English | MEDLINE | ID: mdl-12706477

ABSTRACT

The 5-HT(3) and 5-HT(4) receptor antagonists alosetron and piboserod, and the muscarinic receptor antagonists PNU-171990A (2-(diisopropylamino)ethyl 1-phenylcyclopentanecarboxylate, hydrochloride) and PNU-174708A (2-(diisopropylamino)ethyl 1-phenylcyclohexanecarboxylate) were studied by electromyography, defining the migrating myoelectric complex (MMC) after i.v. administration in conscious rats. Alosetron prolonged the MMC cycle length from 16.6 to maximally 30.4 min at the dose 0.5 mg kg(-1). Piboserod promptly abolished MMC pattern and prolonged cycle length from 16.5 to >60 min at 0.5 mg kg(-1). PNU-171990A and PNU-174708A had no effect on basal cycle length up to a dose of 20 mg kg(-1). In controls, saline did not change the MMC pattern, while L-hyoscyamine at the same dose, 20 mg kg(-1), prolonged cycle length from 17.6 to 29.0 min. None of the drugs affected duration or propagation velocity of phase III of MMC. Blockade of 5-HT(4) receptors seems to exert a powerful inhibitory effect on motility, 5-HT(3) receptor blockade is less efficient and muscarinic receptor blockade has low efficacy.


Subject(s)
Muscarinic Antagonists/pharmacology , Myoelectric Complex, Migrating/drug effects , Serotonin Antagonists/pharmacology , Animals , Atropine/pharmacology , Carbolines/pharmacology , Carboxylic Acids , Cyclopropanes , Dose-Response Relationship, Drug , Electromyography , Esters/pharmacology , Indoles/pharmacology , Intestine, Small/drug effects , Intestine, Small/physiology , Myoelectric Complex, Migrating/physiology , Oxazines/pharmacology , Rats , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/physiology , Receptors, Serotonin, 5-HT3/drug effects , Receptors, Serotonin, 5-HT3/physiology , Receptors, Serotonin, 5-HT4/drug effects , Receptors, Serotonin, 5-HT4/physiology
3.
Ann N Y Acad Sci ; 967: 476-81, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12079877

ABSTRACT

Mammals metabolize citrate to acetyl-CoA and oxaloacetate via the enzyme, ATP:citrate lyase. Bacteria lack this enzyme, but have the ability to cleave citrate in the form of citryl-CoA in an analogous manner using a structurally distinct enzyme. We have identified a novel mammalian gene that shows significant amino acid sequence homology to the bacterial CitE gene product that is responsible for cleavage of citryl-CoA. We propose that this gene encodes an enzyme that catalyzes cleavage of substrates related to CoA esters of citrate or an analogous intermediary metabolite. The product of this novel gene may represent a component of an unknown metabolic pathway in mammals.


Subject(s)
Citric Acid/metabolism , Oxo-Acid-Lyases/metabolism , Amino Acid Sequence , Animals , Humans , Male , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Oxo-Acid-Lyases/chemistry , Sequence Homology, Amino Acid
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