<ul style="margin-right: 0px; margin-bottom: 0px; margin-left: 0px; padding: 0px; list-style: outside none; font-family: Roboto, &quot;helvetica neue&quot;, helvetica, arial, sans-serif; font-size: 16px;"><li class="va-top ov-h" style="margin: 0px 0px 4px; padding: 0px; vertical-align: top; overflow: hidden; zoom: 1;"><span style="font-size: 14px; font-family: Helvetica;"><font color="#000000">Experimental reduction of the nuclear&nbsp;pore&nbsp;numbers&nbsp;decreased&nbsp;nuclear&nbsp;import&nbsp;of signaling proteins, resulting in decreased expression of immediate-early genes. In a&nbsp;mouse&nbsp;model of high blood pressure, the reduction of&nbsp;nuclear&nbsp;pore&nbsp;numbers&nbsp;improved adverse heart remodeling and reduced progression to lethal heart failure.</font></span></li></ul><p><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nuclear-pore" title="Learn more about Nuclear pores from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="font-family: Helvetica; font-size: 14px;">Nuclear pores</span></a><span style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="font-family: Helvetica; font-size: 14px;">&nbsp;are so essential for nuclear-cytoplasmic transport. Whether and also how cells change nuclear pores to alter nuclear transport and cellular function is unknown. Here, we try to show that rat heart muscle cells which mean (cardiomyocytes) undergo a 63% is decrease in nuclear pore numbers during maturation, and this changes their responses to extracellular signals. </span></span></p><p><span style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="font-family: Helvetica; font-size: 14px;">The maturation-associated decline in nuclear pore numbers is associated with the lower nuclear import of signaling proteins such as mitogen-activated protein kinase also known as MAPK. According to the experimental reduction of nuclear pore numbers decreased nuclear import of signaling proteins, resulting in decreased expression of immediate-early genes. In a mouse model of high blood pressure, the reduction of nuclear pore numbers improved adverse heart remodeling and reduced progression to lethal heart failure. The decrease in the nuclear pore numbers in cardiomyocyte maturation and resulting functional changes demonstrate how terminally it is differentiated cells permanently alter their handling of information flux across the&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nuclear-membrane" title="Learn more about nuclear envelope from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">nuclear envelope</span></a><span style="font-family: Helvetica; font-size: 14px;">&nbsp;and, with that, their behavior.</span></span></p><p><span style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><br></span><span style="color: rgb(46, 46, 46); font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px; margin: 0px; padding: 0px;"><span style="margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;">The&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nuclear-membrane" title="Learn more about nuclear envelope from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">nuclear envelope</span></a><span style="margin: 0px; padding: 0px;"><span style="margin: 0px; padding: 0px;"><span style="margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;">&nbsp;is a double&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/phospholipid-bilayer" title="Learn more about phospholipid bilayer from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">phospholipid bilayer</span></a><span style="font-family: Helvetica; font-size: 14px;">&nbsp;that used to separate the nucleus from the cytoplasm.&nbsp;</span></span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nuclear-pore" title="Learn more about Nuclear pores from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">Nuclear pores</span></a><span style="font-family: Helvetica; font-size: 14px;">&nbsp;&nbsp;</span></span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/macromolecule" title="Learn more about transport macromolecules from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">transport macromolecules</span></a><span style="font-family: Helvetica; font-size: 14px;">&nbsp;into and out of the nucleus at a rate of several hundred molecules per second, and this includes&nbsp;</span></span></span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/signal-transduction" title="Learn more about signal transduction from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">signal transduction</span></a><span style="margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;">&nbsp;proteins that regulate&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/genetic-transcription" title="Learn more about gene transcription from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">gene transcription</span></a>.&nbsp;</span></span><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">Whether and how cells alter NPs to modulate the access of signal transduction proteins into nuclei and, with that, their transcriptional and functional responses, is unknown.</span></p><p id="p0050" style="margin-bottom: 16px; padding: 0px; color: rgb(46, 46, 46); font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="font-family: Helvetica; font-size: 14px;">One property that can be assessed is the number of NPS per nucleus. NP numbers are widely between cell types and species: whereas yeasts have approximately 100 NP per nucleus, newt heart cells have approximately 12,000 Maul and Deaven, 1977</span><span style="font-family: Helvetica; font-size: 14px;">. NP numbers are constant in the adult rat liver and brain cells, and this suggests that cells establish the NP numbers for their life when they terminally differentiate between D'Angelo et al.,2009</span><span style="font-family: Helvetica; font-size: 14px;">. We present the observation that heart muscle cells which mean (cardiomyocytes) decrease the number of their NPS during maturation toward the post-mitotic state, and we have provided evidence for the significance of this decrease for nuclear transport and the response of the heart to stress.</span><img src="/media/django-summernote/2022-10-31/e649441c-b515-42e3-82d4-e1641db9433e.png" style="width: 100%;"></p><p id="p0055" style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="font-family: Helvetica; font-size: 14px;"><font color="#2e2e2e">After mammalian cardiomyocytes enter the terminally differentiated state and become post-mitotic, they grow by enlargement (hypertrophy). In mice and rats, this transition occurs within weeks after birth and is indicated by the formation of binucleated cardiomyocytes </font><span style="font-family: Helvetica;"><font color="#000000">(</font></span></span><a name="bbib14" href="https://www.sciencedirect.com/science/article/pii/S1534580722007195#bib14" class="workspace-trigger" style="margin: 0px; padding: 0px; word-break: break-word;"><span style="font-family: Helvetica; font-size: 14px;"><font color="#000000">Kirillova et&nbsp;al., 2021</font></span></a><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">). Although hypertrophy is a mechanism of developmental heart growth, in terminally differentiated cardiomyocytes, cardiac stress induces maladaptive hypertrophy, and this leads to pathological remodeling of the heart, ultimately resulting in heart failure. Cardiac remodeling due to high blood pressure is a significant public health problem Heineke and also Molkentin,2006</span><span style="font-family: Helvetica; font-size: 14px;"><span style="font-family: Helvetica;"><font color="#000000">.</font></span><font color="#2e2e2e"> Cardiac maladaptive remodeling is initiated by extracellular factors that activate G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), which activate intracellular signaling pathways, chiefly the mitogen-activated protein kinase (MAPK) pathways, leading to gene transcription changes&nbsp;&nbsp;</font></span><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">Heineke and also Molkentin,2006</span><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">.</span></p><p id="p0055" style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;"> Although it is cardiac maladaptive signaling at the level of GPCR, RTK, MAPK, and gene transcription is well understood, the fundamental mechanisms which could alter the propagation of these signals into the nucleus to determine the maladaptive response in cardiomyocytes are unknown. We have also developed a hypothesis based on our observation that the number of NPs&nbsp;decreases during cardiomyocyte maturation. We also try to present testing of the hypothesis that the decrease of NP numbers decreases nuclear import of the signaling proteins, and for this changes, adaptive gene transcription, and, with that, improves the cardiac response to stress.</span><img src="/media/django-summernote/2022-10-31/65613237-5dd6-459e-bc5b-d3012739860c.png" style="width: 698.013px;"></p><p id="p0055" style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">Conclusion:</span></p><ul><li style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">Cardiomyocytes decrease their NP numbers during maturation</span></li><li style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">NPs are cylindrical&nbsp;</span><span style="color: rgb(46, 46, 46); margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;">macromolecular complexes of approximately 120–180&nbsp;nm outer diameter. Multiples of ∼34 different proteins, called&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nucleoporin" title="Learn more about nucleoporins from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; text-decoration-line: underline; text-decoration-thickness: 1px; text-decoration-color: rgb(46, 46, 46); color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">nucleoporins</span></a><span style="font-family: Helvetica; font-size: 14px;">&nbsp;(Nups), are assembled into NPs consisting of ∼1,000 Nups.</span></span></li><li style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="color: rgb(46, 46, 46); margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;"> Nups are arranged in 8-fold symmetry around a ∼5&nbsp;nm central opening</span></span><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">. Due to their very large size, individual NPS can be visualized with microscopy. By u</span><span style="color: rgb(46, 46, 46); margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;">sing immunofluorescence&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/confocal-microscopy" title="Learn more about confocal microscopy from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; text-decoration-line: underline; text-decoration-thickness: 1px; text-decoration-color: rgb(46, 46, 46); color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">confocal microscopy</span></a><span style="font-family: Helvetica; font-size: 14px;">, we visualized NPs in less mature (fetal and neonatal) and terminally differentiated adult rat ventricular cardiomyocyte nuclei.</span></span></li><li style="margin-bottom: 16px; padding: 0px; font-family: NexusSerif, Georgia, &quot;Times New Roman&quot;, Times, STIXGeneral, &quot;Cambria Math&quot;, &quot;Lucida Sans Unicode&quot;, &quot;Microsoft Sans Serif&quot;, &quot;Segoe UI Symbol&quot;, &quot;Arial Unicode MS&quot;, serif; font-size: 18px;"><span style="color: rgb(46, 46, 46); font-family: Helvetica; font-size: 14px;">Quantification showed us that the number of NPS per nucleus decreased from 1,856&nbsp;± 66 NPs in fetal (E14.5) to 1,040&nbsp;± 53 in neonatal (P2), and further to 678&nbsp;± 32 in adult (P60) rat cardiomyocytes</span><span style="color: rgb(46, 46, 46); margin: 0px; padding: 0px;"><span style="font-family: Helvetica; font-size: 14px;">. This overall 2.7-fold decrease corresponds to a 63% decline in the&nbsp;</span><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/nuclear-pore" title="Learn more about NP from ScienceDirect's AI-generated Topic Pages" class="topic-link" style="margin: 0px; padding: 0px; text-decoration-line: underline; text-decoration-thickness: 1px; text-decoration-color: rgb(46, 46, 46); color: rgb(46, 46, 46); word-break: break-word; text-underline-offset: 1px;"><span style="font-family: Helvetica; font-size: 14px;">NP</span></a><span style="font-family: Helvetica; font-size: 14px;">&nbsp;number.</span></span></li></ul><p></p>