American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · Oct 2013
SERCA Cys674 sulphonylation and inhibition of L-type Ca2+ influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis.
The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP [produced by soluble guanylyl cyclase (sGC)] versus oxidative posttranslational modifications of Ca(2+) transporters. C57BL/6 mice [wild-type (WT) mice] were administered lipopolysaccharide (LPS; 25 μg/g ip) and euthanized 12 h later. ⋯ After LPS, phospholamban phosphorylation at Ser(16) and Thr(17) was unchanged in WT mice and was increased in sGCα1(-/-) mice. LPS caused sulphonylation of SERCA Cys(674) (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1(-/-) versus WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in L-type Ca(2+) channel function and oxidative posttranslational modifications of SERCA Cys(674), with the latter (at least) being opposed by sGC-released cGMP.
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Am. J. Physiol. Heart Circ. Physiol. · Oct 2013
Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease.
Strong epidemiological and experimental evidence indicate that hypertension in the elderly predisposes to the development of Alzheimer's disease (AD), but the underlying mechanisms remain elusive. The present study was designed to characterize the additive/synergistic effects of hypertension and aging on the expression of genes involved in β-amyloid generation and AD in the hippocampus, an area of brain contributing to higher cognitive function, which is significantly affected by AD both in humans and in mouse models of the disease. To achieve that goal, we induced hypertension in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic (4 wk) infusion of angiotensin II and assessed changes in hippocampal mRNA expression of genes involved in amyloid precursor protein (APP)-dependent signaling, APP cleavage, Aβ processing and Aβ-degradation, synaptic function, dysregulation of microtubule-associated τ protein, and apolipoprotein-E signaling. ⋯ These genes are all involved in the early onset form of AD. Yet, hypertension in aging was associated with changes in hippocampal expression of APP binding proteins, e.g., [Mint3/amyloid β A4 precursor protein-binding family A member 3 (APBA3), Fe65/amyloid β A4 precursor protein-binding family B member 1 (APBB1)], amyloid β (A4) precursor-like protein 1 (APLP1), muscarinic M1 receptor, and serum amyloid P component, all of which may have a role in the pathogenesis of late-onset AD. The hippocampal gene expression signature observed in aged hypertensive mice in the present study provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of AD.
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Am. J. Physiol. Heart Circ. Physiol. · Oct 2013
Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia.
Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. ⋯ RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls (P < 0.01) and on base versus apex (P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.
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Am. J. Physiol. Heart Circ. Physiol. · Oct 2013
Activation of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis attenuates the cardiac reactivity to acute emotional stress.
Recent data indicate the brain angiotensin-converting enzyme/ANG II/AT1 receptor axis enhances emotional stress responses. In this study, we investigated whether its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/ANG-(1-7)/Mas axis, attenuate the cardiovascular responses to acute emotional stress. In conscious male Wistar rats, the tachycardia induced by acute stress (air jet 10 l/min) was attenuated by intravenous injection of ANG-(1-7) [Δ heart rate (HR): saline 136 ± 22 vs. ⋯ Our data show that activation of the ACE2/ANG-(1-7)/Mas axis attenuates stress-induced tachycardia. This effect might be either via the central nervous system reducing anxiety level and/or interfering with the positive chronotropy mediated by activation of cardiac β adrenergic receptors. Therefore, ANG-(1-7) might contribute to reduce the sympathetic load to the heart during situations of emotional stress, reducing the cardiovascular risk.
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Am. J. Physiol. Heart Circ. Physiol. · Sep 2013
Strong linear relationship between heart rate and mean pulmonary artery pressure in exercising patients with severe precapillary pulmonary hypertension.
The contribution of heart rate (HR) to pulmonary artery hemodynamics has been suggested in pulmonary hypertension (PH). Our high-fidelity pressure, retrospective study tested the hypothesis that HR explained the majority of mean pulmonary artery pressure (mPAP) and pulse pressure (PApp) variation in 12 severe precapillary PH patients who performed incremental-load cycling while in the supine position. Seven idiopathic pulmonary arterial hypertension patients and five chronic thromboembolic PH patients were studied. ⋯ PApp was linearly related to mPAP in 12 of 12 patients (median r(2) = 0.985), HR in 10 of 12 patients (median r(2) = 0.97), CO in 7 of 12 patients (median r(2) = 0.87), and SV in 1 of 12 patients. A strong linear relationship between HR and mPAP was consistently documented in severe precapillary PH patients who performed supine exercise. The limited value of thermodilution CO to predict mPAP could be explained by unavoidable precision errors in CO measurements, unchanged/decreased SV on exercise, curvilinearity of the mPAP-CO relationship at high flow, or flow-independent additional mechanisms increasing mPAP on exercise.