Hook3 is a scaffold for the opposite-polarity microtubule-based motors cytoplasmic dynein-1 and KIF1C.

The unidirectional and opposite-polarity microtubule-based motors, dynein and kinesin, drive long-distance intracellular cargo transport. Cellular observations suggest that opposite-polarity motors may be coupled. We recently identified an interaction between the cytoplasmic dynein-1 activating adaptor Hook3 and the kinesin-3 KIF1C. Here, using in vitro reconstitutions with purified components, we show that KIF1C and dynein/dynactin can exist in a complex scaffolded by Hook3. Full-length Hook3 binds to and activates dynein/dynactin motility. Hook3 also binds to a short region in the "tail" of KIF1C, but unlike dynein/dynactin, this interaction does not activate KIF1C. Hook3 scaffolding allows dynein to transport KIF1C toward the microtubule minus end, and KIF1C to transport dynein toward the microtubule plus end. In cells, KIF1C can recruit Hook3 to the cell periphery, although the cellular role of the complex containing both motors remains unknown. We propose that Hook3's ability to scaffold dynein/dynactin and KIF1C may regulate bidirectional motility, promote motor recycling, or sequester the pool of available dynein/dynactin activating adaptors

Brief report: Characteristics of antidepressant use in patients with heart failure

Paul J Mills1, Joel E Dimsdale1, Suzi Hong1, Geoffrey Van Den Brande2, Laura Redwine2, Barry H Greenberg2, Thomas Rutledge11Department of Psychiatry; 2Department of Medicine, University of California San Diego, La Jolla, CA, USABackground: Depression is common in heart failure (HF), but there is little data on the characteristics of antidepressant use in patients with HF.Objective: To survey basic information on antidepressant prescription characteristics, use, effectiveness, and follow-up.Methods: Observational study in two outpatient cardiology clinics of 37 NYHA class I–IV HF patients taking antidepressant medication.Results: Thirty-one percent of prescriptions for antidepressants were obtained from psychiatrists, 58% from primary care physicians, and 8% from cardiologists. The majority of patients (87%) reported regularly taking their antidepressant medication as prescribed, however 48% reported never having had the dosage of their antidepressant medication adjusted. Only 53% of the patients reported that the medication had helped their mood “almost entirely” or “mostly” back to normal since starting their antidepressants, while the remaining patients reported that their mood was only “halfway” or “somewhat” back to normal or that the medication had not helped their depression at all. Among a subset of 10 patients who completed the Beck Depression (BDI) inventory, 6 still had depressed mood (BDI ≥ 10).Conclusion: The findings from this survey study provide insight into the characteristics of antidepressant use in patients with HF and argue for better follow up of HF patients who are prescribed antidepressants.Keywords: heart failure, antidepressant medication, adherence, effectivenes

Depression as a potential modulator of beta-adrenergic -associated leukocyte mobilization in heart failure patients

OBJECTIVES: the aim of this study was to determine whether depressive symptoms are related to alterations in the sensitivity of peripheral blood mononuclear cells to β-adrenergic agonists in patients with heart failure (HF) by measuring in vitro chemotaxis (CTX) to isoproterenol at rest and after acute exercise in patients with HF and controls. BACKGROUND: clinical outcomes are worse for patients with HF presenting with symptoms of depression. Sympathetically modulated immune dysregulation associated with depression may be one mechanism leading to worse prognosis. METHODS: seventy-seven patients with HF and 44 controls (mean age 56.4 ± 1.3 years) completed the Beck Depression Inventory and a 15-min mild-graded exercise task on a stationary bicycle. Exercise intensity was kept relative to fitness levels for all participants by gradually increasing resistance to reach a Borg scale subjective rating of 12 to 13, "somewhat hard." Plasma norepinephrine and epinephrine levels were measured before and after exercise. Chemotaxis to isoproterenol was determined by measuring in vitro peripheral blood mononuclear cell migration through a modified Boyden chamber. RESULTS: In patients with HF, depressive symptom severity was associated with greater CTX after exercise (p = 0.001). Higher resting norepinephrine in patients with HF was also associated with increased CTX to exercise (p = 0.03). CONCLUSIONS: patients with HF with higher depressive symptoms and norepinephrine exhibited increased peripheral blood mononuclear cell CTX to isoproterenol to mild exercise, suggesting greater β-adrenergic sensitivity. Increased immune migration in patients with HF who have elevated depressive symptoms could be associated with cardiac remodeling and HF disease progression

Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) independently predict depressive symptom severity after 12 months in heart failure patients

Objective. To determine whether inflammatory markers prospectively predict depressive symptom severity 12 months later in heart failure (HF) patients. Methods. In 30 HF patients we assessed depressive symptom severity by the Beck depression inventory (BDI) at baseline as well as 12 months later. We measured circulating levels of the soluble intercellular adhesion molecule (sICAM)-1, the cytokine interleukin (IL)-6 and the acute phase protein C-reactive protein (CRP) at baseline assessment. Results. sICAM-1 (r=.38, p=.045) but not CRP or IL-6 correlated with BDI scores 12 months later. Hierarchical linear regression analysis revealed that independent of baseline BDI assessment, cardiovascular risk factors, indicators of HF disease severity, and medication intake, sICAM-1 significantly predicted BDI scores 12 months later. sICAM-1 independently explained between 7% (beta=.26, p=.040) and 10% (beta=.35, p=.045) of the total variance in BDI scores 12 months later. Conclusion. The findings from this exploratory analysis suggest that the adhesion molecule sICAM-1 is an independent predictor of depressive symptoms 12 months later in HF patients. Our prospective findings support the suggested role for inflammation in increasing future depressive symptom severity and extend this linkage for the first time to HF

Effects of Caloric Intake and Aerobic Activity in Individuals with Prehypertension and Hypertension on Levels of Inflammatory, Adhesion and Prothrombotic Biomarkers—Secondary Analysis of a Randomized Controlled Trial

Background: Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been examined so far. Methods: Sixty-eight sedentary prehypertensive and mildly hypertensive individuals (mean age ± SEM: 45 ± 1 years; mean BP: 141/84 ± 1/1 mmHg) were randomized to one of three 12-week intervention groups: cardio training and caloric reduction, cardio training alone, or wait-list control group. Plasma levels of inflammatory, adhesion and prothrombotic biomarkers were assessed. In a second step, intervention groups were combined to one sample and multivariate regression analyses were applied in order to account for exercise and diet behavior changes. Results: There were no significant differences among the intervention groups. In the combined sample, greater caloric reduction was associated with a larger increase of sICAM-3 (p = 0.026) and decrease of C-reactive protein (p = 0.018) as a result of the interventions. More cardio training was associated with increases of sICAM-3 (p = 0.046) as well as interleukin-6 (p = 0.004) and a decrease of tumor necrosis factor-α (p = 0.017) levels. Higher BP predicted higher plasminogen activator inhibitor (PAI)-1 (p = 0.001), and greater fitness predicted lower PAI-1 levels (p = 0.006) after the intervention. Conclusions: In prehypertensive and hypertensive patients, plasma levels of the adhesion molecule sICAM-3 and inflammatory biomarkers have different response patterns to cardio training with and without caloric reduction. Such anti-inflammatory and anti-thrombotic effects may have implications for the prevention of atherothrombotic cardiovascular disease among individuals at increased risk