In utero exposure to nicotine abolishes the postnatal response of the cardiac sodium current to isoproterenol in newborn rabbit atrium.

BACKGROUND: In utero exposure to tobacco smoke is associated with sudden infant death syndrome (SIDS) and cardiac arrhythmias in newborns. The arrhythmogenic mechanisms seem linked to alterations of the cardiac sodium current (INa). We previously reported that in utero exposure to nicotine delays the postnatal development of the heart sinoatrial node in rabbits and altered expression of the sodium channels NaV1.5 and NaV1.1 in the atrium surrounding it. These channels react differently to sympathetic stimulation. OBJECTIVE: The purpose of this study was to test whether nicotine altered the response of INa to stimulation by the ß-adrenoreceptor agonist isoproterenol in atrial myocytes. Our hypothesis is that changes in the sympathetic response of sinoatrial node peripheral cells may create a substrate for arrhythmia. METHODS: Using the patch-clamp technique we measured the effect of nicotine on the response of INa to adrenergic stimulation in isolated cardiomyocytes. RESULTS: Isoproterenol increased INa by 50% in newborn sham rabbits but had no effect in newborn rabbits exposed to nicotine in utero. Our data also show that nicotine increases the late sodium current, an effect that may promote QT prolongation. CONCLUSION: We provide the first evidence linking fetal exposure to nicotine to long-term alterations of INa response to isoproterenol. These changes may impair INa adaptation to sympathetic tone and prevent awakening from sleep apnea, thus leading to arrhythmias that could potentially be involved in SIDS. Our data also raise concerns about the use of nicotine replacement therapies for pregnant women.

In-utero exposure to nicotine alters the development of the rabbit cardiac conduction system and provides a potential mechanism for sudden infant death syndrome.

In-utero exposure to tobacco smoke remains the highest risk factor for sudden infant death syndrome (SIDS). To alleviate the risks, nicotine replacement therapies are often prescribed to women who wish to quit smoking during their pregnancy. Cardiac arrhythmias is considered the final outcome leading to sudden death. Our goal in this study was to determine if exposing rabbit fetus to nicotine altered the cardiac conduction system of newborn kittens in a manner susceptible to cause SIDS. Using neuronal markers and a series of immunohistological and electrophysiological techniques we found that nicotine delayed the development of the cardiac pacemaker center (sinoatrial node) and decreased its innervation. At the molecular level, nicotine favored the expression of cardiac sodium channels with biophysical properties that will tend to slow heart rate and diminish electrical conduction. Our results show that alterations of the cardiac sodium current may contribute to the bradycardia, conduction disturbances and other cardiac arrhythmias often associated to SIDS and raise awareness on the use of replacement therapy during pregnancy.

The histone H3K27 methylation mark regulates intestinal epithelial cell density-dependent proliferation and the inflammatory response.

Polycomb-group proteins form multimeric protein complexes involved in transcriptional silencing. The Polycomb Repressive complex 2 (PRC2) contains the Suppressor of Zeste-12 protein (Suz12) and the histone methyltransferase Enhancer of Zeste protein-2 (Ezh2). This complex, catalyzing the di- and tri-methylation of histone H3 lysine 27, is essential for embryonic development and stem cell renewal. However, the role of Polycomb-group protein complexes in the control of the intestinal epithelial cell (IEC) phenotype is not known. We show that Suz12 and Ezh2 were differentially expressed along the intestinal crypt-villus axis. ShRNA-mediated Suz12 depletion in the IEC-6 rat crypt-derived cell line decreased Ezh2 expression and H3K27 di-trimethylation. Suz12-depleted cells achieved higher cell densities after confluence, with increased cyclin D2 and cyclin D3 protein levels, and increased STAT3 activation in post-confluent cells. Suz12 depletion specifically increased mostly developmental, cell adhesion and immune response gene expression, including neuronal and inflammatory genes. Suz12 depletion directly and indirectly de-regulated the IL-1ß-dependent inflammatory response, as demonstrated by decreased MAPK p38 activation as opposed to JNK activation, and altered basal and stimulated expression of inflammatory genes, including transcription factors such as C/EBPß. Of note, this positive effect on cell proliferation and inflammatory gene expression was revealed in the absence of the cyclin-dependent kinase inhibitor p16, a main target negatively regulated by PRC2. These results demonstrate that the PRC2 complex, in addition to keeping in check non-IEC differentiation pathways, insures the proper IEC response to cell density as well as to external growth and inflammatory signals, by controlling specific signaling pathways.

About half of the late sodium current in cardiac myocytes from dog ventricle is due to non-cardiac-type Na(+) channels.

Voltage gated sodium channels (Na(V)s) are essential to propagate neuronal and cardiac electrical impulses. While the cardiac Na(+) current (I(Na)) is often all attributed to the cardiac isoform, Na(V)1.5, some evidence suggests that other Na(+) channel isoforms are also expressed in the heart ventricle. One way to distinguish Na(+) channels is by their sensitivity to tetrodotoxin (TTX); various "non-cardiac-type" Na(+) channels are relatively sensitive to TTX (denoted tNa(V) channels) compared to Na(V)1.5 channels. tNa(V) channels have been detected in hearts with various pathological conditions such as hypertrophy, infarction and ischemia, where they might enhance the late Na(+) current (I(NaL)) thereby prolonging the action potential under such conditions (resulting in a prolonged QT interval on the EKG). The principal aim of this article is to evaluate the extent to which non-cardiac isotypes contribute to I(NaL) under normal physiological conditions. I(NaL) was measured in acutely dissociated dog cardiomyocytes using the patch-clamp technique. Our results indicate that 44% on average of the late I(Na) current is due to non-cardiac Na(V)s. Previous studies indicated that the overexpression of non-cardiac Na(V) channels is responsible for the prolonged duration of the cardiac action potential (and, thereby, a prolonged QT interval) under pathophysiological conditions associated with various heart diseases. Our finding indicates that non-cardiac Na(V) channels are strong contributors to I(NaL) under physiological conditions thereby suggesting that these channels are also major determinants of the duration of the cardiac action potential even in healthy hearts. Interestingly, these results may explain the observations of cardiac arrhythmias associated with prolonged QT intervals in people with inherited neuronal and musculoskeletal diseases involving mutations that enhance the current from non-cardiac-type Na(V)s, a connection which apparently was never made before.

Modulation of canine cardiac sodium current by Apelin.

Apelin, a ligand of the G protein-coupled putative angiotensin II-like receptor (APJ-R), exerts strong vasodilating, cardiac inotropic and chronotropic actions. Its expression is highly up-regulated during heart failure. Apelin also increases cardiac conduction speed and excitability. While our knowledge of apelin cardiovascular actions is growing, our understanding of the physiological mechanisms behind the cardiac effects remains limited. We tested the effects of apelin on the cardiac sodium current (I(Na)) using patch clamp technique on cardiac myocytes acutely dissociated from dog ventricle. We found that apelin-13 and apelin-17 increased peak I(Na) by 39% and 61% and shifted its mid-activation potential by -6.8+/-0.6 mV and -17+/-1 mV respectively thus increasing channel opening at negative voltage. Apelin also slowed I(Na) recovery from inactivation. The effects of apelin on I(Na) amplitude were linked to activation of protein kinase C. Apelin also increased I(Na) "window" current by up to 600% suggesting that changes in intracellular sodium may contribute to the apelin inotropic effects. Our results reveal for the first time the effects of apelin on I(Na). These effects are likely to modulate cardiac conduction and excitability and may have beneficial antiarrhythmic action in sodium chanelopathies such as Brugada Syndrome where I(Na) amplitude is reduced.