Browsing by Subject "Metabolism"
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Item Interplay between metabolic and myogenic mechanisms in coronary pressure-flow autoregulation(2022-05) Warne, Cooper M.; Tune, Johnathan D.; Dick, Gregory M.; Mallet, Robert T.The local metabolic hypothesis proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure-flow autoregulation. Conversely, the myogenic hypothesis proposes that pressure-induced vascular tone, indexed by the pressure at which coronary flow is zero (Pzf), determines autoregulation. My working hypothesis posits that if metabolism predominates, then autoregulation will be directly related to CvPO2, irrespective of reductions in coronary vasomotor tone. Conversely, if a myogenic mechanism predominates, then autoregulation will be directly related to Pzf, regardless of underlying CvPO2. I tested these hypotheses by examining the extent to which exaggeration of the metabolic error signal and attenuation of myogenic tone influences coronary autoregulation. Experiments were performed in anesthetized, open-chest swine in which a coronary artery was cannulated and connected to a servo-controlled roller pump system. This allowed coronary perfusion pressure (CPP) to be incrementally reduced from 140 to 40 mmHg before and during hypoxemia (SO2 ~50%). CvPO2 decreased 13 mmHg and coronary blood flow fell 57% as CPP was reduced. Hypoxemia augmented myocardial oxygen consumption (P < 0.01), increased coronary blood flow (P < 0.0001), and reduced CvPO2 (P < 0.0001) over the same CPP range. Coronary blood flow during hypoxemia maintained myocardial oxygen delivery (P = 0.20). Hypoxemia increased closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (P = 0.02). Gc was inversely correlated to CvPO2 and Pzf, but the correlation was stronger for CvPO2. These findings support that coronary pressure-flow autoregulation is augmented by hypoxemia-induced increases in the local metabolic error signal, regardless of the myogenic tone.Item Neural Cytoskeleton Modulation after Transient Ischemic Attack and Region-Specific Brain Metabolism Insights(2022-08) Wang, Linshu; Yang, Shaohua; Sumien, Nathalie; Schreihofer, Derek A.; Liu, RanTransient ischemic attack (TIA) is a symptomatic diagnosis disease characterized as reversible ischemic stroke-like neurological deficit. One-third of the TIA patients have recurrent episodes, and TIA presents as a high vascular risk factor for severe stroke, mild cognitive impairment, and dementia. However, the neuropathophysiology of TIA has been less studied. Here, we established recurrent TIA model in rats with no neurological deficits and no/minimal apoptosis cells detected. Our study demonstrated that recurrent TIA induces neuronal cytoskeleton modification, astrogliosis and microgliosis in the TIAaffected cortical and basal ganglia regions, as well as in the white matter in terms of corpus callosum in the acute and subacute stage. Our data indicate recurrent TIA-induced neuronal cytoskeletal modification and neuroinflammation, may be potentially involved in the vascular contribution to cognitive impairment and dementia. Even though neurological deficits are transient in TIA patients, the brain presents morphologic and metabolic change in response to transient ischemic insult. This can be reflected on the remodeling of cytoskeleton, which plays a critical role in the mitochondria shape and motility maintenance. In addition, the interaction between cytoskeletal components and mitochondria is highly involved in the oxidative phosphorylation and mitochondrial respiration regulation. To investigate the brain metabolic signatures in the normal and pathological conditions, our study optimized a method that enables metabolic function assessment of anatomically defined brain structures by the Seahorse XFe96 analyzer in rodents. Our data demonstrated that the rodent brain has region-specific glucose metabolic profile, the cerebellum displays a more quiescent phenotype than cerebral cortex, basal ganglia, and hippocampus. Additionally, the rodent brain has relatively low mitochondrial oxidative phosphorylation efficiency with high proton leaklinked respiration. Through our proof-of-principle study, we expect to acquire critical insights that will enable future research in pursuit of spatial mapping of the brain glucose metabolism in physiological and pathological conditions (e.g., TIA condition), and further explore the mechanisms and significance of mitochondrial uncoupling of the brain.Item The Role of Mitochondrial Respiration in Müller Glia Survival and Function Under Normal and Glaucomatous Conditions In Vivo(2023-05) Nsiah, Nana Yaa; Inman, Denise M.; Stankowska, Dorota L.; Zode, Gulab S.; Yang, ShaohuaSeveral markers of mitochondrial dysfunction have been observed in the retinas of glaucoma patients and experimental animal models. However, these studies have primarily focused on retinal neuron cells even though glial cells too contain significant amounts of mitochondria. Thus, little is known about how glial cell mitochondrial dysfunction contributes to glaucoma pathology. As the principal macroglial cells of the retina, Müller glia (MG) function is essential to maintaining homeostasis in the retina. However, very little is known about how MG generate energy to support their function in vivo. In this study, we address the role of mitochondrial respiration in MG using an inducible Cox10 knockout transgenic mouse model. Cox10 (protoheme IX farnesyltransferase) encodes a component of cytochrome c oxidase (COX), complex IV, of the electron transport chain. Cox10 deficient cells lack functional COX. Disruption of COX function in MG did not affect MG survival nor retinal structure but impaired visual function and upregulated glycolysis pathway protein expression in the retina. These data suggest that MG-specific mitochondrial respiration is essential for whole retinal energy metabolism and visual processing. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be upregulated in the glaucomatous retina and optic nerve, yet its role in glaucoma pathogenesis remains unexplored. HIF-1α is a transcription factor that promotes glycolysis and metabolic adaptation during hypoxia. By blocking HIF-1α degradation through pharmacologic inhibition, we found that prolonged HIF- 1α stabilization led to retinal glycolysis and oxidative phosphorylation (OXPHOS) protein downregulation and AMP-activated protein kinase (AMPK) activation, indicating low energy status. These changes were accompanied by impaired retinal ganglion cell (RGC) function and glial cell activation. Taken together, these results demonstrate the essential role of MG-specific OXPHOS in the retina, as well as pointing to a role for HIF-1α in neurodegeneration in the retina.