Lei Zhou

Bio: Lei Zhou is an academic researcher from The Texas Heart Institute. The author has contributed to research in topics: Medicine & Angiogenesis. The author has an hindex of 4, co-authored 6 publications receiving 224 citations. Previous affiliations of Lei Zhou include Nanjing Medical University.

PI3K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1α expression in MCF-7 breast cancer cells.

Abstract: Background Hypoxia-inducible factor 1 (HIF-1α) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1α in tumor cells remain unknown. Methodology/Principal Findings In this study, we reported that hypoxia could induce HIF-1α and VEGF expression accompanied by Rac1 activation in MCF-7 breast cancer cells. Blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1 (T17N) or Rac1 siRNA downregulated hypoxia-induced HIF-1α and VEGF expression. Furthermore, Hypoxia increased PI3K and ERK signaling activity. Both PI3K inhibitor LY294002 and ERK inhibitor U0126 suppressed hypoxia-induced Rac1 activation as well as HIF-1α expression. Moreover, hypoxia treatment resulted in a remarkable production of reactive oxygen species (ROS). N-acetyl-L-cysteine, a scavenger of ROS, inhibited hypoxia-induced ROS generation, PI3K, ERK and Rac1 activation as well as HIF-1α expression. Conclusions/Significance Taken together, our study demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.

VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways.

Abstract: Angiogenic growth factors, vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) could decrease myocardial infarct size, which was assumed to be related with newly formed capillaries. We doubted that these capillaries could do this solely and the potential protective mechanisms of VEGF and Ang1 on myocardium need to be evaluated. Three types of adenoviruses encoding human VEGF165 (Ad-VEGF165), human angiopoietin-1 (Ad-Ang1) and green fluorescent protein (Ad-GFP, as a parallel control) were constructed. Experiments were taken both in vitro and in vivo. As in vitro, the antiapoptosis effect of VEGF165, Ang1 and VEGF165+Ang1 on cardiac myoblasts was observed, which seemed to be related with the activation of phosphatidylinositol-3 kinase and Bcl-2 pathways. As in vivo, adenoviruses were intramyocardially injected immediately after the ligation of the left anterior descending coronay arteries in rats. The results showed positive effect of VEGF165, Ang1 and VEGF165+Ang1 on decreasing the myocardial infarct size at the 7th day. Myocardial PI-3K activity and Bcl-2 expression were elevated relatively at the 3rd day. The protective effect of VEGF165 and Ang1 on the myocardium may broaden their functional research and contribute to their clinical use in the future.

Endothelial-Like Progenitor Cells Engineered to Produce Prostacyclin Rescue Monocrotaline-Induced Pulmonary Arterial Hypertension and Provide Right Ventricle Benefits

Abstract: Background—Intravenous prostacyclin is approved for treating pulmonary arterial hypertension (PAH), but it has a short half-life and must be delivered systemically via an indwelling intravenous catheter. We hypothesize that localized jugular vein delivery of prostacyclin-producing cells may provide sustained therapeutic effects without the limitations of systemic delivery. Methods and Results—We generated a vector expressing a human cyclooxygenase isoform 1 and prostacyclin synthase fusion protein that produces prostacyclin from arachidonic acid. Endothelial-like progenitor cells (ELPCs) were transfected with the cyclooxygenase isoform 1-prostacyclin synthase plasmid and labeled with lentivirus expressing nuclear-localized red fluorescent protein (nuRFP). The engineered ELPCs (expressing cyclooxygenase isoform 1-prostacyclin synthase and nuRFP) were tested in rats with monocrotaline (MCT)-induced PAH. In PAH prevention studies, treatment with engineered ELPCs or control ELPCs (expressing nuRFP alone) atte...

Cardiac gene activation analysis in mammalian non-myoblasic cells by Nkx2-5, Tbx5, Gata4 and Myocd.

Abstract: Cardiac transcription factors are master regulators during heart development Some were shown to transdifferentiate tail tip and cardiac fibroblasts into cardiomyocytes However, recent studies have showed that controversies exist Potential difference in tail tip and cardiac fibroblast isolation may possibly confound the observations Moreover, due to the use of a cardiac reporter (Myh6) selection strategy for induced cardiomyocyte enrichment, and the lack of tracking signals for each transcription factors, individual roles of each transcription factors in activating cardiac gene expression in mammalian non-myoblastic cells have never been elucidated Answers to these questions are an important step toward cardiomyocyte regeneration Because mouse 10T1/2 fibroblasts are non-myoblastic in nature and can be induced to express genes of all three types of muscle cells, they are an ideal model for the analysis of cardiac and non-cardiac gene activation after induction We constructed bi-cistronic lentiviral vectors, capable of expressing cardiac transcription factors along with different fluorescent tracking signals By infecting 10T1/2 fibroblasts with Nkx2-5, Tbx5, Gata4 or Myocd cardiac transcription factor lentivirus alone or different combinations, we found that only Tbx5+Myocd and Tbx5+Gata4+Myocd combinations induced Myh6 and Tnnt2 cardiac marker protein expression Microarray-based gene ontology analysis revealed that Tbx5 alone activated genes involved in the Wnt receptor signaling pathway and inhibited genes involved in a number of cardiac-related processes Myocd alone activated genes involved in a number of cardiac-related processes and inhibited genes involved in the Wnt receptor signaling pathway and non-cardiac processes Gata4 alone inhibited genes involved in non-cardiac processes Tbx5+Gata4+Myocd was the most effective activator of genes associated with cardiac-related processes Unlike Tbx5, Gata4, Myocd alone or Tbx5+Myocd, Tbx5+Gata4+Myocd activated the fewest genes associated with non-cardiac processes Conclusively, Tbx5, Gata4 and Myocd play different roles in cardiac gene activation in mammalian non-myoblastic cells Tbx5+Gata4+Myocd activates the most cardiac and the least non-cardiac gene expression

Corrigendum to VEGF165 and angiopoietin-1 decreased myocardium infarct size through phosphatidylinositol-3 kinase and Bcl-2 pathways

Abstract: Correction to: Gene Therapy (2005) 12, 196–202. doi:10.1038/sj.gt.3302416 Since publication of the above article, the authors have identified an error in the authorship of the paper. The correct authorship is shown below. L Zhou1, W Ma1*, Z Yang1, F Zhang1, L Lu1, Z Ding1, B Ding1, T Ha1, X Gao2*, CLi1,3*

Angiogenesis and Cardiac Hypertrophy: Maintenance of Cardiac Function and Causative Roles in Heart Failure

Abstract: Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell–cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myo...

Regulation of Hypoxia‐Inducible Factor‐1a by Reactive Oxygen Species : New Developments in an Old Debate

Abstract: Hypoxia-Inducible Factor-1 (HIF-1) has been largely studied for its role in cell survival in hypoxic conditions. The regulation of HIF-1 is a complex process and involves a number of molecules and pathways. Among these mechanisms a direct regulatory role of reactive oxygen species (ROS) on HIF-1 alpha subunit has received a great deal of attention and the existing body of literature includes many contradictory findings. Other intermediates such as nitric oxide (NO), specific microRNAs (miR), and transcriptional and post-translational modification have also been implicated as players in ROS mediated HIF-1a regulation. The focus of this review is to present the past conflicting evidence along with more recent findings in order to relate various aspects of this complex process. Aside from the direct role of ROS on HIF-1a regulation under hypoxia and normoxia, we analyzed the effect of different sources and concentrations of NO and the interplay between superoxide (SO) and NO in this process. We also present findings on transcriptional and translational regulation of HIF-1a via ROS and the interplay with microRNAs in this process. This review further provides insight on ERK and PI3K/AKT signaling as a common mechanism relating several pathways of ROS mediated HIF-1a regulation. Ultimately further research and discovery regarding HIF-1 regulation by oxidative stress is warranted for better understanding of disease development and potential therapeutics for pathologies such as cancer, inflammatory diseases, and ischemia-reperfusion injury.

Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis.

Abstract: A new era has begun in the treatment of ischemic disease and heart failure. With the discovery that stem cells from diverse organs and tissues, including bone marrow, adipose tissue, umbilical cord blood, and vessel wall, have the potential to improve cardiac function beyond that of conventional pharmacological therapy comes a new field of research aiming at understanding the precise mechanisms of stem cell-mediated cardiac repair. Not only will it be important to determine the most efficacious cell population for cardiac repair, but also whether overlapping, common mechanisms exist. Increasing evidence suggests that one mechanism of action by which cells provide tissue protection and repair may involve paracrine factors, including cytokines and growth factors, released from transplanted stem cells into the surrounding tissue. These paracrine factors have the potential to directly modify the healing process in the heart, including neovascularization, cardiac myocyte apoptosis, inflammation, fibrosis, contractility, bioenergetics, and endogenous repair.