In view of the therapeutic potential of cardiomyocytes derived from induced pluripotent stem (iPS) cells (iPS-derived cardiomyocytes), in the present study we investigated in iPS-derived cardiomyocytes, the functional properties related to [Ca2+]i handling and contraction, the contribution of the sarcoplasmic reticulum (SR) Ca2+ release to contraction and the b-adrenergic inotropic responsiveness. The two iPS clones investigated here were generated through infection of human foreskin fibroblasts (HFF) with retroviruses containing the four human genes: OCT4, Sox2, Klf4 and C-Myc. Our major findings showed that iPS-derived cardiomyocytes: (i) express cardiac specific RNA and proteins; (ii) exhibit negative force–frequency relations and mild (compared to adult) post-rest potentiation; (iii) respond to ryanodine and caffeine, albeit less than adult cardiomyocytes, and express the SR-Ca2+ handling proteins ryanodine receptor and calsequestrin. Hence, this study demonstrates that in our cardiomyocytes clones differentiated from HFF-derived iPS, the functional properties related to excitation–contraction coupling, resemble in part those of adult cardiomyocytes.
On the basis of previous findings suggesting that in human embryonic stem cell-derived cardiomyocytes (hESC-CM) the sarcoplasmic reticulum Ca 2؉ -induced release of calcium machinery is either absent or immature, in the present study we tested the hypothesis that hESC-CM contain fully func-
Vagal stimulation inhibits systemic pain perception in animals, probably via the nucleus tractus solitarius and its connections with descending nuclei in the brainstem which inhibit pain. Pain-inhibiting effects of such stimulation in humans, obtained from epileptic patients treated by vagal stimulation, are controversial. The aim of our study was to evaluate whether vagal stomach afferent activation inhibits pain perception in healthy humans. Pain thresholds, magnitude of tonic heat pain at 46 degrees C stimulation, pain temporal summation and laser pain evoked potentials were measured at the hand before and immediately after rapid drinking of 1500 ml water in 31 volunteers. We found an increase in heat pain threshold from 43.3+/-2.6 to 44.7+/-2.2 degrees C, P<0.0001, a decrease of peak pain magnitude to tonic heat from 56.3+/-26.2 to 43.7+/-25.8 (on 0-100 VAS), P<0.0001, a lowering of area under the curve during tonic noxious heat stimulus from 1962+/-984 to 1411+/-934, P<0.001. Additionally, we observed a decrease in the peak to peak evoked potential amplitude from 19.2 microV+/-1.2 to 15.6 microV+/-1.2 (P=0.005) together with a decrease in the estimation of mean laser induced pain from 52.28+/-18.00 to 48.14+/-20.18 (P=0.025). Mechanical pain thresholds and temporal summation did not change significantly. We conclude that vagal stomach afferents exert an inhibitory effect on somatic pain perception in humans.
Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1α expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive control patients and patients with PAH. Compared with controls, HIF-1α and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle cells. Functionally, PASMC contractility was inversely correlated with HIF-1α activity. In PASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E. A., Chen, C.-H., Sedan, O., Cornfield, D. N. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.
Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administrationapproved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptoticinducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicininduced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 M, 24 h) prevented doxorubicin (0.5 M, 24 h)-induced elevation of diastolic [Ca 2ϩ ] i , the slowing of [Ca 2ϩ ] i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca 2ϩ ) ATPase, Na ϩ /Ca 2ϩ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/ dt max ) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.
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