PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin.

MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the down-regulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin- and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks.

Left atrial diameter, aortic mean gradient, and hemoglobin for risk stratification in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an alternative treatment of severe symptomatic aortic stenosis (AS) in patients with high operative risk. In spite of favorable entire results, long-term mortality of patients is high. HYPOTHESIS: The present study aims to identify independent preprocedural risk factors to improve risk stratification in these highly selected patients. METHODS: This prospective study included 202 consecutive patients with severe symptomatic AS and high operative risk (mean logistic European System for Cardiac Operative Risk Evaluation, 22±17%; mean age, 79±6 years; 107 female). Preprocedural comprehensive examinations were performed (laboratory, electrocardiography, echocardiography, cardiac catheterization). All patients received transfemoral or transaxillary TAVI with a CoreValve prosthesis (Medtronic, Minneapolis, MN). RESULTS: During a follow-up of 535±333 days, 56 patients (28%) reached the primary study end point (all-cause mortality). Independent predictors of long-term mortality were as follows: hemoglobin<12.5 g/dL (hazard risk [HR], 3.62; 95% confidence interval [CI], 2.025-6.468; P<0.001), aortic mean gradient≤41 mm Hg (HR, 2.16; 95% CI, 1.272-3.655; P=0.004), and left atrial diameter>42 mm (HR, 3.09; 95% CI, 1.588-6.019; P=0.001). Our risk-stratification model based on these independent predictors separated patients into 4 groups with high (74%), intermediate (37%), low (18%), and very low (3%) all-cause mortality. CONCLUSIONS: In patients undergoing TAVI, preprocedural assessment of hemoglobin, aortic mean gradient, and left atrial diameter provides independent prognostic information and therefore contributes to improved risk stratification in TAVI.