Browsing by Subject "Stress, Mechanical"
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Item Exercise Pressor Reflex Dysfunction in Hypertension(2009-09-04) Leal, Anna Katherine; Smith, Scott AlanThe exercise pressor reflex and its components, the muscle mechanoreflex and the metaboreflex, are overactive in hypertension. The mechanoreflex and metaboreflex are feedback mechanisms originating in skeletal muscle that increase mean arterial pressure (MAP) and heart rate (HR) during exercise. In hypertensive individuals, mechanoreflex and metaboreflex overactivity can cause dangerous elevations in MAP and HR during physical activity, creating risks for adverse cardiac events. Mechanoreflex (predominantly group III) and metaboreflex (predominantly group IV) afferent fibers, which are activated by mechanical stress and the metabolic byproducts of working muscle, respectively, project to the nucleus tractus solitarius (NTS) in the brainstem. Within this nucleus, nitric oxide (NO) is produced from L-arginine via the enzymatic activity of nitric oxide synthase (NOS). Brainstem NO has been shown to modulate exercise pressor reflex-driven changes in MAP and HR. Therefore, we hypothesized that a decrease in NO production/availability within the NTS is involved in mediating both mechanoreflex and metaboreflex dysfunction in hypertension. To test this, we microdialyzed a NOS inhibitor, L-nitro-arginine methyl ester (L-NAME), and the NO precursor, L-arginine, into the NTS of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats to experimentally alter endogenous NO production during preferential activation of mechanically and metabolically sensitive skeletal muscle afferents. Passive hindlimb muscle stretch was the maneuver used to simulate mechanoreflex activation while metabolically sensitive afferents were activated by hindlimb intra-arterial capsaicin injections. Capsaicin binds to transient potential 1 (TRPv1) receptors, which are primarily localized to group IV afferents. We found that blocking NO production via L-NAME within the NTS of normotensive WKY rats recapitulates the exaggerated cardiovascular response elicited by both mechanically and metabolically sensitive afferent neurons in hypertension. Importantly, we demonstrated that experimentally increasing NO production within the NTS of hypertensive SHR rats partially corrects the enhanced cardiovascular response to activation of both mechanically and metabolically sensitive afferent neurons. These findings provide evidence that a decrease in NO production/availability within the brainstem contributes to mechanoreflex and metaboreflex dysfunction in hypertension. Future utilization of this research could lead to effective treatment options for hypertensive individuals, allowing them to engage in physical activity without the associated hemodynamic risks.Item Phosphatase Regulation of Mechanical Stress and Aging in C. elegans(2020-08-01T05:00:00.000Z) Egge, Nathan Chandler; Goldsmith, Elizabeth J.; Douglas, Peter; Mendell, Joshua T.; Terman, Jonathan R.; Joachimiak, LukaszStress and aging embody two related processes driving cellular dysfunction. In either case, environmental stimuli and genetically encoded regulatory mechanisms affect cellular homeostasis and influence adaptation. Phosphatases represent master regulators of stress signaling and modulate cellular responses and fate during stress and aging. Yet, physiologically relevant mechanisms by which these phosphatases are regulated or orchestrate stress response and lifespan are incompletely understood. Herein, I present two scenarios, mechanical trauma and intestinal aging, both of which involve regulation by phosphatases. Mechanical stimuli initiate adaptive signal transduction pathways, but exceeding cell tolerance for physical stress results in degeneration and death via unclear mechanisms. In the nematode C. elegans, I developed a model to study cellular degeneration in response to mechanical stress caused by blunt force trauma. I identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and itself is dually regulated by its target, KGB-1. KGB-1 both activates VHP-1 via a negative feedback loop and represses via inhibition of a deubiquitinase, MATH-33, affecting proteasomal degradation. Thus, I describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity. Like stress, aging challenges cell tolerances, instigating death upon inadequacy of homeostatic regulation. Intestinal cells form a vital barrier separating environment from organism. Age impairs intercellular interactions and the cells' capacity to tightly associate within tissues and form an effective barrier necessary for normal systemic function. In particular, the actin cytoskeleton represents a key determinant in maintaining tissue architecture; how age disrupts the actin cytoskeleton, and, in turn, promotes mortality remains unclear. Herein, I show that phosphorylation of ACT-5 compromises C. elegans intestinal barrier integrity and accelerates pathogenesis. Age-related loss of the heat shock transcription factor, HSF-1, disrupts the Jun kinase/Protein Phosphatase I equilibrium, increasing ACT-5 phosphorylation within a troponin-binding site. Phosphorylated ACT-5 accelerates decay of the intestinal terminal web and impairs cell junctions. Therefore, age-associated dysregulation of phosphatase/kinase activity contributes to intestinal dysmorphogenesis and organism death.