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Mermis J.,University of Kansas Medical Center | Gu H.,University of Kansas Medical Center | Xue B.,University of Kansas Medical Center | Li F.,University of Kansas Medical Center | And 6 more authors.
Respiratory Research | Year: 2011

Background: Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH.Methods: The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB.Results: HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CMmediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB.Conclusion: In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH. © 2011 Mermis et al; licensee BioMed Central Ltd. Source


Mason B.L.,University of Texas Southwestern Medical Center | Lobo M.K.,323 Harry Hines Blvd | Parada L.F.,University of Maryland, Baltimore | Lutter M.,University of Texas Southwestern Medical Center
Obesity | Year: 2013

Objective Loss of BDNF-TrkB signaling results in obesity in both humans and mice; however, the neural circuit that mediates this effect is unknown. The role of TrkB signaling in dopamine-1 receptor expressing neurons in body weight regulation was tested. Methods Mice with a floxed allele of the TrkB gene were paired with mice expressing Cre-recombinase under control of the D1 promoter to conditionally knock out expression of TrkB receptors from D1-neurons. Results Deletion of TrkB receptors from D1 neurons results in obesity in chow fed mice due to increased feed efficiency. In contrast, loss of Trk B signaling in D1 neurons induced hyperphagia and hyperglycemia in mice maintained on high fat diet. Conclusions These findings indicate TrkB signaling in D1 neurons regulates body weight by distinct mechanisms for chow and high fat diet and may be important for defending the body against the development of obesity and obesity-related disorders. Copyright © 2013 The Obesity Society. Source


Huang J.,323 Harry Hines Blvd | Davis E.C.,McGill University | Chapman S.L.,323 Harry Hines Blvd | Budatha M.,323 Harry Hines Blvd | And 3 more authors.
Circulation Research | Year: 2010

Rationale: Loss of fibulin-4 during embryogenesis results in perinatal lethality because of aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers. Objective: We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic development. Methods And Results: We generated germline and smooth muscle cell (SMC)-specific deletion of the fibulin-4 gene in mice (Fbln4 and Fbln4, respectively). Fbln4 and Fbln4 aortic walls fail to fully differentiate, exhibiting reduced expression of SM-specific contractile genes and focal proliferation of SMCs accompanied by degenerative changes of the medial wall. Marked upregulation of extracellular signal-regulated kinase 1/2 signaling pathway was observed in the aneurysmal wall of Fbln4 and Fbln4 mice and both mutants developed aneurysm predominantly in the ascending thoracic aorta. In vitro, Fbln4 SMCs exhibit an immature SMC phenotype with a marked reduction of SM-myosin heavy chain and increased proliferative capacity. Conclusions: The vascular phenotype in Fbln4 mutant mice is remarkably similar to a subset of human thoracic aortic aneurysms caused by mutations in SMC contractile genes. Our study provides a potential link between the intrinsic properties of SMCs and aneurysm progression in vivo and supports the dual role of fibulin-4 in the formation of elastic fibers as well as terminal differentiation and maturation of SMCs in the aortic wall. © 2010 American Heart Association, Inc. Source


Small E.M.,323 Harry Hines Blvd | Sutherland L.B.,323 Harry Hines Blvd | Kinoshita H.,Clinical science | Gerard R.D.,323 Harry Hines Blvd | And 4 more authors.
Circulation Research | Year: 2010

Rationale: Myocardial infarction (MI) results in loss of cardiac myocytes in the ischemic zone of the heart, followed by fibrosis and scar formation, which diminish cardiac contractility and impede angiogenesis and repair. Myofibroblasts, a specialized cell type that switches from a fibroblast-like state to a contractile, smooth muscle-like state, are believed to be primarily responsible for fibrosis of the injured heart and other tissues, although the transcriptional mediators of fibrosis and myofibroblast activation remain poorly defined. Myocardin-related transcription factors (MRTFs) are serum response factor (SRF) cofactors that promote a smooth muscle phenotype and are emerging as components of stress-responsive signaling. Objective: We aimed to examine the effect of MRTF-A on cardiac remodeling and fibrosis. Methods and results: Here, we show that MRTF-A controls the expression of a fibrotic gene program that includes genes involved in extracellular matrix production and smooth muscle cell differentiation in the heart. In MRTF-A-null mice, fibrosis and scar formation following MI or angiotensin II treatment are dramatically diminished compared with wild-type littermates. This protective effect of MRTF-A deletion is associated with a reduction in expression of fibrosis-associated genes, including collagen 1a2, a direct transcriptional target of SRF/MRTF-A. Conclusions: We conclude that MRTF-A regulates myofibroblast activation and fibrosis in response to the renin-angiotensin system and post-MI remodeling. © 2010 American Heart Association, Inc. Source

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