期刊：
AMERICAN JOURNAL OF PATHOLOGY,2013年182(3):886-894 ISSN：0002-9440
通讯作者：
Tanowitz, HB
作者机构：
[Weiss, Louis M.; Desruisseaux, Mahalia S.; Zhao, Dazhi; Factor, Stephen M.; Tanowitz, Herbert B.; Nagajyothi, Fnu; Huang, Huan] Albert Einstein Coll Med, Dept Pathol, Div Parasitol & Trop Med, Bronx, NY 10461 USA.;[Kuliawat, Regina] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA.;[Weiss, Louis M.; Desruisseaux, Mahalia S.; Tanowitz, Herbert B.; Singh, Rajat; Schwartz, Gary J.; Pessin, Jeffrey E.] Albert Einstein Coll Med, Dept Med, Div Infect Dis, Bronx, NY 10461 USA.;[Weiss, Louis M.; Desruisseaux, Mahalia S.; Tanowitz, Herbert B.; Singh, Rajat; Schwartz, Gary J.; Pessin, Jeffrey E.] Albert Einstein Coll Med, Dept Med, Div Endocrinol, Bronx, NY 10461 USA.;[Singh, Rajat; Schwartz, Gary J.; Pessin, Jeffrey E.] Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10461 USA.
通讯机构：
[Tanowitz, HB ] A;Albert Einstein Coll Med, Dept Pathol, 1300 Morris Pk Ave, Bronx, NY 10461 USA.
摘要：
Chagas disease, caused by Trypanosoma cruzi, is an important cause of morbidity and mortality primarily resulting from cardiac dysfunction, although T. cruziin fection results in inflammation and cell destruction in many organs. We found that T. cruzi (Brazil strain) infection of mice results in pancreatic inflammation and parasitism within pancreatic beta-cells with apparent sparing of a cells and leads to the disruption of pancreatic islet architecture, beta-cell dysfunction, and surprisingly, hypoglycemia. Blood glucose and insulin levels were reduced in infected mice during acute infection and insulin levels remained low into the chronic phase. In response to the hypoglycemia, glucagon levels 30 days postinfection were elevated, indicating normal a-cell function. Administration of L-arginine and a beta-adrenergic receptor agonist (CL316, 243, respectively) resulted in a diminished insulin response during the acute and chronic phases. Insulin granules were docked, but the lack of insulin secretion suggested an inability of granules to fuse at the plasma membrane of pancreatic beta-cells. In the liver, there was a concomitant reduced expression of glucose-6-phosphatase mRNA and glucose production from pyruvate (pyruvate tolerance test), demonstrating defective hepatic gluconeogenesis as a cause for the T. cruzi-induced hypoglycemia, despite reduced insulin, but elevated glucagon levels. The data establishes a complex, multi-tissue relationship between T. cruzi infection, Chagas disease, and host glucose homeostasis. (Am 3 Pathol 2013, 182:886-894; http:// dx.doi.org/10.1016/j.ajpath.2012.11.027)
摘要：
Previously, we found that G protein-coupled receptor APJ endogenous ligand apelin-13 stimulates vascular smooth muscle cells (VSMC) proliferation mediated in part by PKC-PI3K-ERK1/2-cyclinDl signaling cascades. In this study, Raf-1-14-3-3 signaling in rat VSMCs proliferation stimulated by apelin-13 was further investigated. Cell proliferation was measured with MTT assay. Expression of PI3K, phospho-PI3K, Raf-1, phospho-Raf-1, ERK1/2, phospho-ERKl/2, cyclinDl and cyclinE were detected by Western blotting. 14-3-3 protein combining with Raf-1 was detected by immunoprecipitation. Here, we demonstrated that apelin-13 increased the expression of 14-3-3, Raf-1 phosphorylation and ERK1/2 phosphorylation in a concentration- dependent and time-dependent manner at 0~4 μmol/L and 0~48 h. 14-3-3 inhibitor Difopein decreased the apelin-13-induced Raf-1 phosphorylation, ERK1/2 phosphorylation, expression of cyclinDl and cyclinE. Furthermore, apelin-13 promoted the combination of 14-3-3 protein and Raf-1, Difopein significantly inhibited the combination of 14-3-3 and Raf-1 stimulated by apelin-13. Similarly, Difopein significantly inhibited the VSMCs proliferation stimulated by apelin-13. Our results revealed that Raf-1 +14-3-3-ERK1/2 signaling cascades mediated the effect of apelin-13 on rat VSMCs proliferation.
摘要：
Apelin is the endogenous ligand of the G protein-coupled receptor, APJ. Vascular smooth muscle cells express both apelin and APJ, which are important regulatory factors in the cardiovascular and nervous systems. Importantly, APJ is also involved in the pathogenesis if HIV-1 infection. We investigated whether vascular smooth muscle cell proliferation was regulated through an apelin-pERK1/2-cyclin D1 signal transduction pathway. Apelin-13 significantly stimulated vascular smooth muscle cell proliferation and increased cell cycle progression. Apelin-13 a decreased the proportion of cell in the G0/G1 phase while increasing the number of cells in S phase. Apelin-13 also increased the levels of cyclin D1, cyclin E and pERK1/2. Treatment of cells with the MEK inhibitor PD98059 attenuated the apelin-3-induced pERK1/2 activation. Similarly, treatment with PD98059 partially diminished the apelin-13-induced expression of cyclin D1 and vascular smooth muscle cell proliferation. Taken together, these data established that apelin-13 stimulates vascular smooth muscle cell proliferation by promoting the G1-S phase transition, and that this effect is mediated in part by an apelin-pERK1/2-cyclin D1 signal cascade.
