American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · Jun 2017
Comparative StudyDiminished responsiveness to dobutamine as an inotrope in mice with cecal ligation and puncture-induced sepsis: attribution to phosphodiesterase 4 upregulation.
Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. ⋯ We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support. NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac β1-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.
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Am. J. Physiol. Heart Circ. Physiol. · Jun 2017
Toll-like receptor 2 dominance over Toll-like receptor 4 in stressful conditions for its detrimental role in the heart.
It has been suggested that Toll-like receptor (TLR)4 promotes IL-10-mediated cardiac cell survival, whereas another receptor, TLR2, from the same family, is detrimental. Here, we examined the interactive role of these two innate signaling molecules under stressful conditions, including IL-10 knockout (IL-10-/-) mice, global ischemia-reperfusion (I/R) injury in rat hearts, and in vitro short hairpin RNA experimental models in the presence or absence of IL-10 (10 ng/ml). Circulating and myocardial levels of TNF-α as well as apoptosis and fibrosis were higher in IL-10-/- mice. ⋯ The IL-10 mitigation of these changes suggests that the stimulation through TLR4 signaling promotes IRAK-4 and phosphorylates IRAK-1 instead of IRAK-2 and may be an important therapeutic approach in restoring heart health in stress. NEW & NOTEWORTHY Under stress conditions such as downregulation of the IL-10 gene or ischemia-reperfusion injury, Toll-like receptor (TLR)4 and IL-1 receptor-associated kinase (IRAK)-1 activation is suppressed, along with the upregulation of TLR-2 and IRAK-2, resulting in fibrosis and apoptosis. It is suggested that IL-10 helps to maintain heart function during stress via myeloid differentiation gene 88/IRAK-4/IRAK-1-dependent TLR4 signaling.
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Am. J. Physiol. Heart Circ. Physiol. · May 2017
Angiotensin-(1-7) attenuates angiotensin II-induced cardiac hypertrophy via a Sirt3-dependent mechanism.
The objectives of the present study were to investigate the effect of ANG-(1-7) on the development of cardiac hypertrophy and to identify the intracellular mechanism underlying this action of ANG-(1-7). Blood pressure and heart rate were recorded using radiotelemetry before and after chronic subcutaneous infusion of control (PBS), ANG II, ANG-(1-7), or ANG II + ANG-(1-7) for 4 wk in normotensive rats. Chronic administration of ANG-(1-7) did not affect either basal blood pressure or the ANG II-induced elevation in blood pressure. ⋯ Thus, activation of the ANG-(1-7)/Sirt3 signaling pathway could be a novel therapeutic strategy in the management of cardiac hypertrophy and associated complications. NEW & NOTEWORTHY Chronic subcutaneous ANG-(1-7) has no effect on ANG II-induced elevations in blood pressure but significantly attenuates ANG II-induced cardiac hypertrophy and fibrosis by a mitochondrial ROS-dependent mechanism. This protective effect of ANG-(1-7) against the action of ANG II action is mediated by stimulation of sirtuin-3-mediated deacetylation of FoxO3a, which triggers SOD2 expression.
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Am. J. Physiol. Heart Circ. Physiol. · Apr 2017
Optogenetic identification of hypothalamic orexin neuron projections to paraventricular spinally projecting neurons.
Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested (n = 34). ⋯ This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function. NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not GABAergic, neurotransmission in these pathways.
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Am. J. Physiol. Heart Circ. Physiol. · Apr 2017
Right ventricular metabolism during venoarterial extracorporeal membrane oxygenation in immature swine heart in vivo.
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides hemodynamic rescue for patients encountering right or left ventricular (RV or LV) decompensation, particularly after surgery for congenital heart defects. ECMO, supported metabolically by parenteral nutrition, provides reductions in myocardial work and energy demand and, therefore, enhances functional recovery. The RV must often assume systemic ventricular pressures and function on weaning from VA-ECMO. ⋯ These data suggest that the RV shows decreased ability to modify substrate utilization and achieve improvements in energy supply/demand during VA-ECMO. NEW & NOTEWORTHY We showed that the right ventricle unloaded by venoarterial extracorporeal membrane oxygenation (VA-ECMO) has diminished capacity to alter substrate utilization compared with the left ventricle. This decrease in metabolic flexibility contributes to the inability to increase high-energy phosphate reserves during myocardial rest by VA-ECMO.