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Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell
Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell
Physiology Faculty Publications
Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the …
Steroid Binding To Autotaxin Links Bile Salts And Lysophosphatidic Acid Signalling, Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P. Joosten, Manjula Sunkara, Andrew J. Morris, Elisa Matas-Rico, Wouter H. Moolenaar, Ronald P. Oude Elferink, Anastassis Perrakis
Steroid Binding To Autotaxin Links Bile Salts And Lysophosphatidic Acid Signalling, Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P. Joosten, Manjula Sunkara, Andrew J. Morris, Elisa Matas-Rico, Wouter H. Moolenaar, Ronald P. Oude Elferink, Anastassis Perrakis
Gill Heart & Vascular Institute Faculty Publications
Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors …