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- Chen, Y, et al.
(författare)
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Increase in insulin-like growth factor I in hypertrophying smooth muscle
- 1994
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Ingår i: American Journal of Physiology - Endocrinology and Metabolism. - 1522-1555. ; 266:2 Pt 1, s. 224-229
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Tidskriftsartikel (refereegranskat)abstract
- The present study focuses on the role of the insulin-like growth factor (IGF) system in the development of smooth muscle hypertrophy. Hypertrophy was initiated by partial ligation of portal vein or urethra in female Sprague-Dawley rats weighing approximately 220 g. Levels of mRNA were analyzed by solution hybridization. Seven days after ligation, the wet weight of the portal vein was increased about threefold and the concentration of IGF-I mRNA was increased fourfold. The bladder wet weight was increased twofold 3 days after ligation and fourfold 10 days after ligation. IGF-I mRNA in the bladder was elevated 3-fold after 3 days and 2.5-fold after 10 days, whereas IGF binding protein 2 mRNA was increased approximately 2-fold after 3 days and 5-fold after 10 days. IGF-I receptor mRNA in the hypertrophying bladder remained unchanged. Increased levels of IGF-I were demonstrated with immunohistochemistry in both hypertrophying portal vein and urinary bladder. The results show a specific increase in IGF-I mRNA as well as an increased IGF-I immunoreactivity during hypertrophy of smooth muscle, which suggests that the local IGF-system may play a role in smooth muscle hypertrophy.
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| 2. |
- Nilsson, Ulrika K., 1969-
(författare)
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Lysophosphatidic acid : Physiological effects and structure-activity relationships
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lipids havepreviously been considered primarily as building blocks of the cell membrane, but are now also recognized as important cell signaling molecules. Lysophosphatidic acid (LPA) is a glycerophospholipid consisting of a phosphate head group, a linker region, and a lipophilic tail. LPA has earlier been shown to exert a diversity of cellular effects such as aggregation, apoptosis, contraction, migration, and proliferation. The effects of LPA are elicited by activation of its cognate G protein-coupled receptors LPA1, LPA2, and LPA3. In the present study we have used cultures of human smooth muscle cells (SMCs) and erythroleukemia cells (HEL), and isolated human platelets to characterize physiological effects of LPA compared with adrenaline and noradrenaline as well as structure-activity relationships of LPA. SMCs were isolated from biopsies of human myometrium obtained at cesarean sections. We show that cultured myometrial SMCs express multiple LPA and α2-adrenergic receptor subtypes. Treatment of SMCs with LPA and noradrenaline resulted in increases in proliferation. However, LPA elicits a much more pronounced stimulatory effect than noradrenaline. The ability to increase calcium might be one explanation why LPA is more effective. Further studies indicated that several pathways mediate the growth stimulatory effect of LPA where transactivation of epidermal growth factor receptors through matrix metalloproteinases as well as calcium/calmodulin-dependent protein kinases appears to be important. LPA enantiomers and LPA analogues were synthesized and characterized due to their capacity to increase calcium in HEL cells. Our study is the first to show that both natural (R) and unnatural (S) LPA enantiomers are capable of stimulating cells, suggesting LPA receptors are not stereoselective. Moreover, we have synthesized a LPA analogue with higher maximal effect than LPA by reducing the hydrocarbon chain length. In platelets we demonstrated that LPA is a weak calciumelevating compound which failed to stimulate aggregation. However, in combination with adrenaline, another weak platelet agonist, a complete aggregatory response was obtained in blood from some healthy individuals. These results are important since platelet activation is a key step in distinguishing normal from pathological hemostasis. Since LPA is present at high concentrations in atherosclerotic lesions, the synergistic effect of LPA and adrenaline might be a new risk factor for arterial thrombosis.
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