Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways.
Animals; Cell Movement/physiology; Cells; Cultured; Gene Expression Regulation/physiology; Humans; Inbred C57BL; Janus Kinase 2/*biosynthesis; Knockout; Leptin/*physiology; Male; MAP Kinase Signaling System/*physiology; Mice; Muscle; Myocytes; Smooth; Smooth Muscle/enzymology/metabolism; Thrombospondin 1/*biosynthesis; Up-Regulation/*physiology; Vascular/enzymology/*metabolism
Hyperleptinemia, characteristic of diabetes and a hallmark feature of human obesity, contributes to the increased risk of atherosclerotic complications. However, molecular mechanisms mediating leptin-induced atherogenesis and gene expression in vascular cells remain incompletely understood. Accumulating evidence documents a critical role of a potent antiangiogenic and proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in atherosclerosis. Although previous studies reported elevated TSP-1 levels in both diabetic and obese patients and rodent models, there is no direct information on TSP-1 expression in vascular cells in response to leptin. In the present study, we show that leptin upregulates TSP-1 expression in cultured human aortic smooth muscle cells (HASMC) in vitro, and this increase occurs at the level of transcription, revealed by mRNA stability and TSP-1 promoter-reporter assays. Utilizing specific pharmacological inhibitors and siRNA approaches, we demonstrate that upregulation of TSP-1 expression by leptin is mediated by JAK2/ERK/JNK-dependent mechanisms. Furthermore, we report that while ERK and JNK are required for both the constitutive and leptin-induced expression of TSP-1, JAK-2 appears to be specifically involved in leptin-mediated TSP-1 upregulation. Finally, we found that increased HASMC migration and proliferation in response to leptin is significantly inhibited by a TSP-1 blocking antibody, thereby revealing the physiological significance of leptin-TSP-1 crosstalk. Taken together, these findings demonstrate, for the first time, that leptin has a direct regulatory effect on TSP-1 expression in HASMCs, underscoring a novel role of TSP-1 in hyperleptinemia-induced atherosclerotic complications.
Chavez Ronaldo J; Haney Rebecca M; Cuadra Rene H; Ganguly Rituparna; Adapala Ravi K; Thodeti Charles K; Raman Priya
American journal of physiology. Cell physiology
2012
2012-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpcell.00008.2012" target="_blank" rel="noreferrer noopener">10.1152/ajpcell.00008.2012</a>
Neuropathic pain in aged rats: behavioral responses and astrocytic activation.
Aging/*physiology; Animal; Animal/*physiology; Animals; Astrocytes/*metabolism; Behavior; Cell Count; Disease Models; Functional Laterality/physiology; Glial Fibrillary Acidic Protein/metabolism; Hyperalgesia/physiopathology; Immunohistochemistry; Inbred F344; Lumbar Vertebrae; Male; Nerve Crush/methods; Neuralgia/*metabolism/pathology/physiopathology; Pain Measurement; Peripheral Nervous System Diseases/*metabolism/pathology/physiopathology; Posterior Horn Cells/*metabolism; Rats; Thermosensing/physiology; Touch/physiology; Up-Regulation/*physiology
We used the Bennett and Xie (1988) model of chronic neuropathic pain to study the effect of age on thermal and tactile sensitivity and on astrocytic activation in the dorsal horn of the spinal cord after nerve injury. Fischer 344 FBNF1 hybrid rats in three age groups, 4-6, 14-16, and 24-26 months, were studied. Rats were either unligated (day 0, control) or the left sciatic nerve was loosely ligated to cause a chronic constriction injury (CCI). CCI causes a neuropathic pain condition characterized by tactile allodynia and thermal hyperalgesia. Rats were behaviorally assessed for tactile and thermal sensitivity of their ligated and unligated hind paws up to 35 days postligation. Rats were sacrificed before or at various days postligation, and activated astrocytes were identified at the L4-L5 levels of their spinal cords by use of an antibody to glial fibrillary acid protein (GFAP). The number of GFAP-ir astrocytes in the dorsal horn of the spinal cord in the control, uninjured condition decreased with age (P \textless or = 0.001) but increased after CCI in all three age groups. After CCI, astrocytic activation in the cord was less robust in aged rats than in younger ones (P \textless or = 0.01). Not all the CCI rats displayed hyperalgesia to touch and to heat. Rats with an increased sensitivity to heat had increased levels of GFAP-ir in their cords; however, rats with decreased thermal sensitivity also displayed increased
Stuesse S L; Crisp T; McBurney D L; Schechter J B; Lovell J A; Cruce W L
Experimental brain research
2001
2001-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s002210000630" target="_blank" rel="noreferrer noopener">10.1007/s002210000630</a>