Jun N-terminal kinase inhibitor blocks angiogenesis by blocking VEGF secretion and an MMP pathway.
ABSTRACT The excessive proliferation and migration of vascular smooth muscle cells (SMCs) and angiogenesis of endothelial cells (ECs) participate in the growth and instability of atherosclerotic plaques. It is unclear whether Jun N-terminal kinase (JNK) is pro-or anti-atherogenic.
We examined the direct effect of JNK inhibitor (JNK-I) on the proliferation and formation of tubes by human coronary SMCs and human coronary ECs.
Culture medium from JNK-I-treated SMCs prevented ECs from forming tubes in an in vitro model of angiogenesis indirectly by reducing the amount of vascular endothelial growth factor (VEGF) released from SMCs. In addition, JNK-I attenuated the expression of pro-matrix metalloproteinase-2 in ECs. When added back to the medium of SMCs treated with JNK-I, VEGF blocked the inhibitory effect on the formation of tubes.
Our results indicate JNK-I to have a direct anti-atherogenic effect in SMCs and ECs.
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ABSTRACT: Islet transplantation success depends on the number and quality of islets transplanted. This study aimed at exploring the molecular mechanisms associated with cold pancreas preservation and their impact on islet cell survival and function. Rat pancreata were stored in cold University of Wisconsin preservation solution for short (3 hr; control) or long (18 hr) cold ischemia times (CIT). Pancreata exposed to long CIT yielded lower islet numbers and showed reduced cellular viability; isolated islets displayed higher levels of phosphorylated stress-activated protein kinase (c-jun N-terminal Kinase and Mitogen-Activated Protein Kinase-p38), and chemokine (C-C) ligand-3, and lower levels of vascular endothelial growth factor, interleukins (IL)-9 and IL-10. Islets obtained from long-CIT pancreata were functionally impaired after transplantation. Differential proteomic expression in pancreatic tissue after CIT included increased eukaryotic translation elongation factor-1-alpha-1 (apoptosis related) and reduced Clade-B (serine protease inhibitor). Our study indicates that cold ischemia stimulates inflammatory pathways (chemokine (c-c)ligand-3, phosphorylation of c-jun N-terminal Kinase and mitogen-activated protein kinase-p38, and eukaryotic translation elongation factor-1-alpha-1) and decreases repair/cytoprotective pathways (IL-10, vascular endothelial growth factor, and Clade-B), all of which may negatively affect the quality and mass of islets obtained from a donor pancreas.Transplantation 06/2009; 87(10):1442-50. DOI:10.1097/TP.0b013e3181a36b1e · 3.78 Impact Factor
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ABSTRACT: Pathophysiologic responses in brain after stroke are highly complex. Thus far, a singular focus on saving neurons alone has not revealed any clinically effective neuroprotectants. To address this limitation, the concept of a neurovascular unit was developed. Within this conceptual framework, brain function and dysfunction are manifested at the level of cell-cell signaling between neuronal, glial and vascular elements. For stroke, coordinated responses at the neurovascular interface will mediate acute as well as chronic events in ischemic and hemorrhagic brain tissue. In this minireview, we briefly survey two representative examples of neurovascular responses in stroke. During the early acute phase of neurovascular injury, blood-brain barrier perturbations should predominate with key roles for various matrix proteases. During the delayed phase, brain angiogenesis may provide the critical neurovascular substrates for neuronal remodeling. In this minireview, we propose the hypothesis that the biphasic nature of neurovascular responses represents an endogenous attempt by damaged parenchyma to trigger brain angiogenesis and repair. This phenomenon may allow acute deleterious signals to transition into beneficial effects during stroke recovery. Understanding how neurovascular signals and substrates make the transition from initial injury to angiogenic recovery will be important if we are to find new therapeutic approaches for stroke.FEBS Journal 08/2009; 276(17):4644-52. DOI:10.1111/j.1742-4658.2009.07176.x · 3.99 Impact Factor
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ABSTRACT: Angiogenesis is a process during which endothelial cells divide and migrate to form new capillaries from the preexisting blood vessels. The present study was designed to investigate whether MAPKs (mitogen-activated protein kinases) play crucial roles in regulating EGF (epidermal growth factor)-induced endothelial cell angiogenesis. Our results showed that EGF stimulated HUVEC (human umbilical vein endothelial cells) proliferation in a concentration-dependent manner, of which the maximum effective concentration of EGF was 10 ng/ml. Western blot analysis showed that EGF at 10 ng/ml significantly induced the phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1 and 2) and p38 kinase at 5 min, while it induced the phosphorylation of JNK/SAPK (c-Jun N-terminal kinase/stress-activated protein kinase) at 15 min. Further results showed that a JNK/SAPK inhibitor, SP600125, and a specific siRNA JNK/SAPK could both significantly inhibit EGF-induced tube formation in HUVEC cells, and an ERK1/2 inhibitor PD098059 could also block the tube formation in some content, while a p38 inhibitor SB203580 failed to do so. Furthermore, only SP600125 significantly inhibited EGF-induced HUVEC cell proliferation under no cytotoxic concentration, so did JNK/SAPK siRNA. In conclusion, JNK/SAPK and ERK1/2 signals therefore play critical roles in EGF-mediated HUVEC cell angiogenesis.Cell Biology International 12/2010; 34(12):1213-8. DOI:10.1042/CBI20100185 · 1.64 Impact Factor