Abstract-LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima, and induces enhanced migration of SMCs in vitro via its upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. In this study, we have delineated the mechanism by which LR11 elevates the expression levels of uPAR in SMCs. Secretion of soluble LR11 is induced in SMCs during the rapidly proliferating phase, and the secreted LR11 induces the migration activities of SMCs. Both the cell-anchored and secreted forms of LR11 have the capacity to bind to and form complexes with uPAR. LR11-overexpressing cells show significantly enhanced uPAR binding, but decreased uPAR internalization. LR11 colocalizes with uPAR on the cell surface and inhibits the LDL receptor-related protein (
Medial-to-intimal migration of
Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes carboxylation of acetyl-CoA to form malonylCoA. In mammals, two isozymes exist with distinct physiological roles: cytosolic ACC1 participates in de novo lipogenesis (DNL), and mitochondrial ACC2 is involved in negative regulation of mitochondrial -oxidation. Since systemic ACC1 null mice were embryonic lethal, to clarify the physiological role of ACC1 in hepatic DNL, we generated the liver-specific ACC1 null mouse by crossbreeding of an Acc1 lox(ex46) mouse, in which exon 46 of Acc1 was flanked by two loxP sequences and the liver-specific Cre transgenic mouse. In liver-specific ACC1 null mice, neither hepatic Acc1 mRNA nor protein was detected. However, to compensate for ACC1 function, hepatic ACC2 protein and activity were induced 1.4 and 2.2 times, respectively. Surprisingly, hepatic DNL and malonyl-CoA were maintained at the same physiological levels as in wild-type mice. Furthermore, hepatic DNL was completely inhibited by an ACC1/2 dual inhibitor, 5-tetradecyloxyl-2-furancarboxylic acid. These results strongly demonstrate that malonyl-CoA from ACC2 can access fatty acid synthase and become the substrate for the DNL pathway under the unphysiological circumstances that result with ACC1 disruption. Therefore, there does not appear to be strict compartmentalization of malonyl-CoA from either of the ACC isozymes in the liver.Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, which is a key molecule in the control of intracellular fatty acid metabolism (13,16,27). ACC has two major isozymes that have different physiological roles based on their distinct subcellular distributions (2). A cytosolic enzyme, ACC1 (ACC␣; molecular mass, 265 kDa), supplies malonyl-CoA to fatty acid synthase (FAS) and is committed to de novo lipogenesis (DNL) in many tissues via subsequent nutritional and hormonal regulation (3,16,27). In contrast, ACC2 (ACC; molecular mass, 280 kDa) is anchored to the mitochondrial surface via a unique N-terminal domain that includes 20 hydrophobic amino acids (1, 2). ACC2 produces malonyl-CoA on the mitochondrial surface. It is well known that malonylCoA is a potent endogenous inhibitor of carnitine palmitoyl transferase 1 (CPT-1), which is also located on the mitochondrial surface (21, 26). Thus, ACC2 indirectly prevents the influx of fatty acids into the mitochondria and their subsequent -oxidation (4).ACC1 is ubiquitously expressed in many tissues, but higher levels occur in lipogenic tissues, including the liver and adipose tissue (8). In fact, in animals, Acc1 gene expression and ACC activity are markedly induced either by high carbohydrate feeding or hyperinsulinemia in animals and result in increases in adiposity, lipoprotein secretion, and hepatic fat content (16). It is expected that ACC1 blockade should reduce flux through the DNL pathway in lipogenic tissues and thus reduce adiposity, lipoprotein secretion, and fatty liver (11,23). It is therefore plausible that ACC1 inh...
Human Girardi heart cells expressing endothelin ET(B) receptors (GH(B) cells) were transfected with human ET(A) cDNA, and coexpression of ET(A) and ET(B) in the ratio of 4:6 was demonstrated by Scatchard analysis. [125I]Endothelin (ET)-1 binding to ET(A)-transfected GH cells (GH(AB) cells) was displaced by an ET(A) antagonist, BQ-123, in a biphasic manner. An ET(B) agonist, BQ-3020, and an ET(B) antagonist, BQ-788, inhibited [125I]ET-1 binding to GH(AB) cells in a monophasic manner with low affinities (IC50 = 2,800 and 890 nM, respectively); IC50 values for ET(B) receptors seemed to be as weak as those for ET(A) receptors. However, BQ-3020 and BQ-788 had a high affinity for ET(B) receptors in a binding experiment using [125I]ET-1 in the presence of 1 microM BQ-123, where ET(A) receptors are masked (IC50 = 0.49 and 0.89 nM, respectively). The ET(B)-mediated increase in intracellular calcium concentrations in GH(AB) cells was not affected by 0.1 microM BQ-788 alone but was inhibited significantly by the same concentration of BQ-788 in combination with 10 microM BQ-123. ET-1 suppressed forskolin-stimulated accumulation of cAMP through the activation of ET(A) and ET(B) in GH(AB) cells; 1 microM BQ-123 or BQ-788 inhibited the suppression by only 20%, whereas a mixture of BQ-123 and BQ-788 (1 microM each) completely inhibited the cAMP decrease. These findings suggest that the stimulation of ET(A) receptors with ET-1 results in a lowering of the affinity of BQ-3020 and BQ-788 for ET(B) receptors in GH(AB) cells. We conclude that there is intracellular cross-talk between ET(A) and ET(B) receptors in GH(AB) cells.
The CC chemokines may play an important role in the pathogenesis of chronic inflammatory diseases including rheumatoid arthritis, and their effects are thought to be mediated through CCR1 receptors. Several nonpeptide CCR1 receptor antagonists that showed high affinity for human CCR1 receptors have been identified; however, their effectiveness in animal models of inflammatory diseases has been scarcely demonstrated, probably due to species selectivity of the antagonists. To elucidate the pathophysiological role of CCR1 receptors in murine models of disease, we looked for a potent antagonist for both murine and human CCR1 receptors. Screening of our chemical collection for inhibition of (125)I-MIP-1alpha binding to human CCR1 receptors transfected in CHO cells led to the identification of xanthene-9-carboxamide 1a as the lead compound. Derivatization of 1a by quaternarizing the piperidine nitrogen with various alkyl groups and by installing substituents into the xanthene moiety dramatically improved the inhibitory activity against both human and murine CCR1 receptors. As a result, 2q-1 showing IC(50) values of 0.9 and 5.8 nM for human and murine CCR1 receptors, respectively, was discovered. This compound is the first murine CCR1 receptor antagonist and may be a useful tool for clarifying the role of CCR1 receptors in murine models of disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.