PubMed · 13040413
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C FIELDS. 1953. Constriction ring dystocia.. https://doi.org/10.1016/0002-9378(53)90619-x
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The molecular mechanisms leading to high-altitude pulmonary hypertension (HAPH) remains poorly understood. We previously analyzed the whole genome sequence of Kyrgyz highland population and identified eight genomic intervals having a potential role in HAPH. Tropomodulin 3 gene (TMOD3), which encodes a protein that binds and caps the pointed ends of actin filaments and inhibits cell migration, was one of the top candidates. Here we systematically sought additional evidence to validate the functional role of TMOD3. In-silico analysis reveals that some of the SNPs in HAPH associated genomic intervals were positioned in a regulatory region that could result in alternative splicing of TMOD3. In order to functionally validate the role of TMOD3 in HAPH, we exposed Tmod3-/+ mice to 4 weeks of constant hypoxia, i.e. 10% O2 and analyzed both functional (hemodynamic measurements) and structural (angiography) parameters related to HAPH. The hemodynamic measurements, such as right ventricular systolic pressure, a surrogate measure for pulmonary arterial systolic pressure, and right ventricular contractility (RV- ± dP/dt), increases with hypoxia did not separate between Tmod3-/+ and control mice. Remarkably, there was a significant increase in the number of lung vascular branches and total length of pulmonary vascular branches (P < 0.001) in Tmod3-/+ after 4 weeks of constant hypoxia as compared with controls. Notably, the Tmod3-/+ endothelial cells migration was also significantly higher than that from the wild-type littermates. Our results indicate that, under chronic hypoxia, lower levels of Tmod3 play an important role in the maintenance or neo-vascularization of pulmonary arteries.
Calpains are a family of non-lysosomal cysteine proteases. Recent studies have identified a member of the calpain family of proteases, calpain 10, as a putative diabetes-susceptibility gene that may be involved in the development of type 2 diabetes. Inhibition of calpain activity has been shown to reduce insulin-stimulated glucose uptake in isolated rat-muscle strips and adipocytes. In this report, we examine the mechanism by which calpain affects insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Inhibition of calpain activity resulted in approx. a 60% decrease in insulin-stimulated glucose uptake. Furthermore, inhibition of calpain activity prevented the translocation of insulin-responsive glucose transporter 4 (GLUT4) vesicles to the plasma membrane, as demonstrated by fluorescent microscopy of whole cells and isolated plasma membranes; it did not, however, alter the total GLUT4 protein content. While inhibition of calpain did not affect the insulin-mediated proximal steps of the phosphoinositide 3-kinase pathway, it did prevent the insulin-stimulated cortical actin reorganization required for GLUT4 translocation. Specific inhibition of calpain 10 by antisense expression reduced insulin-stimulated GLUT4 translocation and actin reorganization. Based on these findings, we propose a role for calpain in the actin reorganization required for insulin-stimulated GLUT4 translocation to the plasma membrane in 3T3-L1 adipocytes. These studies identify calpain as a novel factor involved in GLUT4 vesicle trafficking and suggest a link between calpain activity and the development of type 2 diabetes.
Proteins interacting with the human PDGF (platelet-derived growth factor) beta-receptor were isolated using immobilized peptides derived from the receptor C-terminus as a bait. We identified two PDZ domain proteins, namely NHERF (Na(+)/H(+) exchanger regulatory factor, also called EBP50) and NHERF2 (E3KARP, SIP-1, TKA-1), which have been shown previously to associate with the murine PDGF receptor [Maudsley, Zamah, Rahman, Blitzer, Luttrell, Lefkowitz and Hall (2000) Mol. Cell. Biol. 20, 8352-8363]. In porcine aortic endothelial cells and in fibroblasts, NHERF recruitment was induced by PDGF treatment, but the receptor kinase activity was not required for the formation of the complex, suggesting that NHERF was not recruited in a phosphotyrosine-dependent manner. Instead, the interaction was abolished by mutation of the consensus C-terminal PDZ-interacting domain of the receptor (Leu-1106 to Ala), or truncation of the last 75 amino acid residues of the receptor. Disruption of NHERF binding to the receptor enhanced actin filament reorganization, but did not affect PDGF-induced mitogenicity and chemotaxis. Although NHERF was initially characterized as a factor required for intracellular pH regulation by beta2-adrenergic receptors, we observed that it was not involved in pH regulation by PDGF. Collectively, these results suggest that the ligand-induced association of NHERF PDZ domain with the PDGF receptor tyrosine kinase controls the extent of cytoskeleton reorganization in response to PDGF.