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<h3></h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>474 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>3 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/15?content=articles&page=2">2</a></li> <li><a href="/tags/15?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/15?content=articles&page=47">47</a></li> <li><a href="/tags/15?content=articles&page=48">48</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/15?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186628">HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186628">Yan Zhang, … , Liping Xie, Yong Ji</a> <a class='hide-for-small show-more' data-reveal-id='article45952-more' href='#'> <div class='article-authors'> Yan Zhang, … , Liping Xie, Yong Ji </div> </a> <span class='article-published-at'> Published April 8, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186628">https://doi.org/10.1172/JCI186628</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186628">Text</a> | <a href="/articles/view/186628/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186628' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45952-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186628">HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186628">Text</a></li> <li><a class="button tiny" href="/articles/view/186628/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Aortic aneurysm is a high-risk cardiovascular disease without effective cure. Vascular Smooth Muscle Cell (VSMC) phenotypic switching is a key step in the pathogenesis of aortic aneurysm. Here, we revealed the role of histidine triad nucleotide-binding protein 1 (HINT1) in aortic aneurysm. HINT1 was upregulated both in aortic tissue from patients with aortic aneurysm and Ang II-induced aortic aneurysm mice. VSMC-specific HINT1 deletion alleviated aortic aneurysm via preventing VSMC phenotypic switching. With the stimulation of pathological factors, the increased nuclear translocation of HINT1 mediated by nucleoporin 98 (Nup98) promoted the interaction between HINT1 and transcription factor AP-2 alpha (TFAP2A) and further triggered the transcription of integrin alpha 6 (ITGA6) mediated by TFAP2A, and consequently activated the downstream focal adhesion kinase (FAK)/STAT3 signal pathway, leading to aggravation of VSMC phenotypic switching and aortic aneurysm. Importantly, Defactinib treatment was demonstrated to limit aortic aneurysm development by inhibiting the FAK signal pathway. Thus, HINT1/ITGA6/FAK axis emerges as potential therapeutic strategies in aortic aneurysm.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yan Zhang, Wencheng Wu, Xuehui Yang, Shanshan Luo, Xiaoqian Wang, Qiang Da, Ke Yan, Lulu Hu, Shixiu Sun, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Feng Chen, Aihua Gu, Liansheng Wang, Zhiren Zhang, Bo Yu, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186146">Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186146">Kevin D Mangum, … , Scott M. Damrauer, Katherine Gallagher</a> <a class='hide-for-small show-more' data-reveal-id='article45905-more' href='#'> <div class='article-authors'> Kevin D Mangum, … , Scott M. Damrauer, Katherine Gallagher </div> </a> <span class='article-published-at'> Published March 27, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186146">https://doi.org/10.1172/JCI186146</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186146">Text</a> | <a href="/articles/view/186146/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186146' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45905-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186146">Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186146">Text</a></li> <li><a class="button tiny" href="/articles/view/186146/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating SMC function in HTN, we considered Genome Wide Association Studies (GWAS) of blood pressure, focusing on genes encoding epigenetic enzymes, which control SMC fate in cardiovascular disease. Using statistical fine mapping of the KDM6 (JMJD3) locus, we found that rs62059712 is the most likely casual variant, with each major T allele copy associated with a 0.47 mmHg increase in systolic blood pressure. We show that the T allele decreased JMJD3 transcription in SMCs via decreased SP1 binding to the JMJD3 promoter. Using our unique SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased EDNRB expression and increased EDNRA expression. Importantly, the Endothelin Receptor A antagonist, BQ-123, reversed HTN after Jmjd3 deletion in vivo. Additionally, single cell RNA-sequencing (scRNA-seq) of human arteries revealed strong correlation between JMJD3 and EDNRB in SMCs. Further, JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs increased HTN-induced arterial remodeling. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing targets that may be used in personalized management of HTN.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kevin D Mangum, Qinmengge Li, Katherine Hartmann, Tyler M Bauer, Sonya J. Wolf, James Shadiow, Jadie Y. Moon, Emily Barrett, Amrita Joshi, Gabriela Saldana de Jimenez, Sabrina A. Rocco, Zara Ahmed, Rachael Bogle, Kylie Boyer, Andrea Obi, Frank M Davis, Lin Chang, Lam Tsoi, Johann Gudjonsson, Scott M. Damrauer, Katherine Gallagher</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179262">Long non-coding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179262">Ke Liao, … , Ahmed G.E. Ibrahim, Eduardo Marbán</a> <a class='hide-for-small show-more' data-reveal-id='article45837-more' href='#'> <div class='article-authors'> Ke Liao, … , Ahmed G.E. Ibrahim, Eduardo Marbán </div> </a> <span class='article-published-at'> Published March 25, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI179262">https://doi.org/10.1172/JCI179262</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179262">Text</a> | <a href="/articles/view/179262/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179262' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45837-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179262">Long non-coding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179262">Text</a></li> <li><a class="button tiny" href="/articles/view/179262/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Regulatory T (Treg) cells modulate immune responses and attenuate inflammation. Extracellular vesicles from human cardiosphere-derived cells (CDC-EVs) enhance Treg proliferation and IL10 production, but the mechanisms remain unclear. Here we focus on BCYRN1, a long noncoding RNA (lncRNA) highly abundant in CDC-EVs, and its role in Treg cell function. BCYRN1 acts as a "microRNA sponge," inhibiting miR-138, miR-150, and miR-98. Suppression of these miRs leads to increased Treg cell proliferation via ATG7-dependent autophagy, CCR6-dependent Treg migration, and enhanced Treg IL10 production. In a mouse model of myocardial infarction, CDC-EVs, particularly those overexpressing BCYRN1, were cardioprotective, reducing infarct size and troponin I levels even when administered after reperfusion. Underlying the cardioprotection, we verified that CDC-EVs overexpressing BCYRN1 increased cardiac Treg infiltration, proliferation, and IL10 production in vivo. These salutary effects were negated when BCYRN1 levels were reduced in CDC-EVs, or when Tregs were depleted systemically. Thus, we have identified BCYRN1 as a booster of Treg number and bioactivity, rationalizing its cardioprotective efficacy. While here we studied BCYRN1 overexpression in the context of ischemic injury, the same approach merits testing in other disease processes (e.g., autoimmunity or transplant rejection) where increased Treg activity is a recognized therapeutic goal.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ke Liao, Jiayi Yu, Akbarshakh Akhmerov, Zahra Mohammadigoldar, Liang Li, Weixin Liu, Natasha Anders, Ahmed G.E. Ibrahim, Eduardo Marbán</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180900">Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180900">Aida Collado, … , Zhichao Zhou, John Pernow</a> <a class='hide-for-small show-more' data-reveal-id='article45885-more' href='#'> <div class='article-authors'> Aida Collado, … , Zhichao Zhou, John Pernow </div> </a> <span class='article-published-at'> Published March 20, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI180900">https://doi.org/10.1172/JCI180900</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180900">Text</a> | <a href="/articles/view/180900/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180900' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45885-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180900">Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180900">Text</a></li> <li><a class="button tiny" href="/articles/view/180900/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the vessel is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following co-incubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase 1 knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial injury mediated by RBCs in T2D.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Aida Collado, Rawan Humoud, Eftychia Kontidou, Maria Eldh, Jasmin Swaich, Allan Zhao, Jiangning Yang, Tong Jiao, Elena Domingo, Emelie Carlestål, Ali Mahdi, John Tengbom, Ákos Végvári, Qiaolin Deng, Michael Alvarsson, Susanne Gabrielsson, Per Eriksson, Zhichao Zhou, John Pernow</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188743">Differential aortic aneurysm formation provoked by chemogenetic oxidative stress</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188743">Apabrita Ayan Das, … , Taylor A. Covington, Thomas Michel</a> <a class='hide-for-small show-more' data-reveal-id='article45878-more' href='#'> <div class='article-authors'> Apabrita Ayan Das, … , Taylor A. Covington, Thomas Michel </div> </a> <span class='article-published-at'> Published March 18, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI188743">https://doi.org/10.1172/JCI188743</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188743">Text</a> | <a href="/articles/view/188743/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188743' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45878-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188743">Differential aortic aneurysm formation provoked by chemogenetic oxidative stress</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188743">Text</a></li> <li><a class="button tiny" href="/articles/view/188743/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Aortic aneurysms are potentially fatal focal enlargements of the aortic lumen; the disease burden disease is increasing as the human population ages. Pathological oxidative stress is implicated in development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line DAAO-TGTie2 that expresses yeast D-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TGTie2 mice, DAAO generates the reactive oxygen species hydrogen peroxide (H2O2) in endothelial cells only when provided with D-amino acids. When DAAO-TGTie2 mice are chronically fed D-alanine, the animals become hypertensive and develop abdominal but not thoracic aortic aneurysms. Generation of H2O2 in the endothelium leads to oxidative stress throughout the vascular wall. Proteomic analyses indicate that the oxidant-modulated protein kinase JNK1 is dephosphorylated by the phophoprotein phosphatase DUSP3 in abdominal but not thoracic aorta, causing activation of KLF4-dependent transcriptional pathways that trigger phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocks aneurysm formation caused by chemogenetic oxidative stress. These studies establish that regional differences in oxidant-modulated signaling pathways lead to differential disease progression in discrete vascular beds, and identify DUSP3 as a potential pharmacological target for the treatment of aortic aneurysms.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, Taylor A. Covington, Thomas Michel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186673">TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186673">Dayu He, … , Tingting Zhang, Hui Huang</a> <a class='hide-for-small show-more' data-reveal-id='article45841-more' href='#'> <div class='article-authors'> Dayu He, … , Tingting Zhang, Hui Huang </div> </a> <span class='article-published-at'> Published March 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186673">https://doi.org/10.1172/JCI186673</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186673">Text</a> | <a href="/articles/view/186673/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186673' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45841-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186673">TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186673">Text</a></li> <li><a class="button tiny" href="/articles/view/186673/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) has been recognized as the principal mechanism underlying vascular calcification (VC). Runt-related transcription factor 2 (RUNX2) in VSMCs plays a pivotal role because it constitutes an essential osteogenic transcription factor for bone formation. As a key DNA demethylation enzyme, ten-eleven translocation 2 (TET2) is crucial in maintaining the VSMC phenotype. However, whether TET2 involves in VC progression remains elusive. Here we identified a substantial downregulation of TET2 in calcified human and mouse arteries, as well as human primary VSMCs. In vitro gain- and loss-of function experiments demonstrated TET2 regulated VC. Subsequently, in vivo knockdown of TET2 significantly exacerbated VC in both vitamin D3 and adenine-diet-induced chronic kidney disease (CKD) mice models. Mechanistically, TET2 binds to and suppresses the activity of the P2 promoter within the RUNX2 gene, whereas an enzymatic loss-of-function mutation of TET2 has a comparable effect. Furthermore, TET2 forms a complex with histone deacetylases 1/2 (HDAC1/2 ) to deacetylate H3K27ac on the P2 promoter, thereby inhibiting its transcription. Moreover, SNIP1 is indispensable for TET2 to interact with HDAC1/2 to exert inhibitory effect on VC, and knockdown of SNIP1 accelerated VC in mice. Collectively, our findings imply that TET2 might serve as a potential therapeutic target for VC.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Dayu He, Jianshuai Ma, Ziting Zhou, Yanli Qi, Yaxin Lian, Feng Wang, Huiyong Yin, Huanji Zhang, Tingting Zhang, Hui Huang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/187711">Macrophage-mediated interleukin-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/187711">Joshua A. Keefe, … , Dobromir Dobrev, Xander H. T. Wehrens</a> <a class='hide-for-small show-more' data-reveal-id='article45833-more' href='#'> <div class='article-authors'> Joshua A. Keefe, … , Dobromir Dobrev, Xander H. T. Wehrens </div> </a> <span class='article-published-at'> Published March 6, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI187711">https://doi.org/10.1172/JCI187711</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/187711">Text</a> | <a href="/articles/view/187711/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI187711' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45833-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/187711">Macrophage-mediated interleukin-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/187711">Text</a></li> <li><a class="button tiny" href="/articles/view/187711/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Postoperative atrial fibrillation (poAF) is AF occurring days after surgery with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA sequencing comparing atrial non-myocytes from mice with versus without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a top gene in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra conditional knockout (cKO) prevented poAF in mice. Downstream STAT3 inhibition with TTI-101 and cardiomyocyte-specific Stat3 cKO rescued poAF, indicating a pro-arrhythmogenic role of STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered a novel link between STAT3 and CaMKII-mediated ryanodine receptor-2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, non-phosphorylatable RyR2S2814A mice were protected from poAF, and CaMKII inhibition prevented arrhythmogenic Ca2+ mishandling in ACMs from mice with poAF. Altogether, we provide multiomic, biochemical, and functional evidence from mice and humans that IL-6-STAT3-CaMKII signaling driven by infiltrating atrial macrophages is a pivotal driver of poAF that portends therapeutic utility for poAF prevention.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Joshua A. Keefe, Yuriana Aguilar-Sanchez, Jose Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A. Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H. Shen, Mihail G. Chelu, Li Na, Dobromir Dobrev, Xander H. T. Wehrens</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/174081">An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/174081">Ping Wang, … , Sakthivel Sadayappan, Hesham A. Sadek</a> <a class='hide-for-small show-more' data-reveal-id='article45769-more' href='#'> <div class='article-authors'> Ping Wang, … , Sakthivel Sadayappan, Hesham A. Sadek </div> </a> <span class='article-published-at'> Published February 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/4">135(4)</a>:e174081. <a href="https://doi.org/10.1172/JCI174081">https://doi.org/10.1172/JCI174081</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/174081">Text</a> | <a href="/articles/view/174081/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI174081' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/174081/figure/1' ref='group' title='Structure characterization of WT and ΔK210 complex. (A) Fluorescence-based measurement of the binding affinity of Ca2+ for WT and K210del to troponin complex. (B) Representation of the overall structure of ΔK210 and WT complex. TnnC is shown in green, TnnT is shown in orange, and TnnI is shown in purple. Ca2+ is shown in pink sphere. This color scheme is consistent for the ΔK210 complex in all the following figures unless otherwise specified. (C) Representation showing superimposition of WT (gray) and ΔK210. (D) Surface representation colored by the vacuum electrostatic potential of WT in the same orientation as in C. (E) Surface representation colored by the vacuum electrostatic potential of the ΔK210 complex in the same orientation as in C. (F) Highlight of K210 deletion site (in green dash circle) and hinge region of TnnT and TnnI showing superimposition of WT (gray) and ΔK210 (TnnC in green, TnnT in orange, and TnnI in purple). Specific residues in the hinge region are shown in stick representation. (G) Representation showing superimposition of Ca2+-binding domains in WT (gray) and ΔK210 (TnnC in green, TnnT in orange and TnnI in purple). (H) Detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in ΔK210 complex. Specific residues coordinating the Ca2+are shown in green stick representation. Hydrogen bonds are indicated with black dashed lines. (I) Detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in WT complex. Specific residues coordinating the Ca2+are shown in gray stick representation. Hydrogen bonds are indicated with black dashed lines. (J) Representation showing superimposition of the detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in WT complex (gray) and ΔK210 complex (green). Data are presented as mean ± SEM; unpaired 2-sided t test. ****P < 0.0001.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/174000/174081/small/JCI174081.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45769-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/174081">An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/174081">Text</a></li> <li><a class="button tiny" href="/articles/view/174081/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell–derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ping Wang, Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen, Ivan Menendez-Montes, Ching-Cheng Hsu, Ayman B. Farag, Suwannee Thet, Nicholas T. Lam, Janaka P. Wansapura, Eric Crossley, Ning Ma, Shane Rui Zhao, Tiejun Zhang, Sachio Morimoto, Rohit Singh, Waleed Elhelaly, Tara C. Tassin, Alisson C. Cardoso, Noelle S. Williams, Hayley L. Pointer, David A. Elliott, James W. McNamara, Kevin I. Watt, Enzo R. Porrello, Sakthivel Sadayappan, Hesham A. Sadek</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/175972">TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/175972">Yihui Li, … , Hao Wang, Ming Zhong</a> <a class='hide-for-small show-more' data-reveal-id='article45758-more' href='#'> <div class='article-authors'> Yihui Li, … , Hao Wang, Ming Zhong </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI175972">https://doi.org/10.1172/JCI175972</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/175972">Text</a> | <a href="/articles/view/175972/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI175972' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45758-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/175972">TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/175972">Text</a></li> <li><a class="button tiny" href="/articles/view/175972/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in endoplasmic reticulum (ER) stress in chronic renal disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress-induced tribble 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX Family Transcription Factor 2 (Runx2) and SMAD Family Member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic knockout of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for chronic renal disease.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/163730">Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/163730">Moydul Islam, … , Kartik Mani, Abhinav Diwan</a> <a class='hide-for-small show-more' data-reveal-id='article45759-more' href='#'> <div class='article-authors'> Moydul Islam, … , Kartik Mani, Abhinav Diwan </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI163730">https://doi.org/10.1172/JCI163730</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/163730">Text</a> | <a href="/articles/view/163730/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI163730' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45759-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/163730">Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/163730">Text</a></li> <li><a class="button tiny" href="/articles/view/163730/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Moydul Islam, David R. Rawnsley, Xiucui Ma, Walter Navid, Chen Zhao, Xumin Guan, Layla Foroughi, John T. Murphy, Honora Navid, Carla J. Weinheimer, Attila Kovacs, Jessica Nigro, Aaradhya Diwan, Ryan P. Chang, Minu Kumari, Martin E. Young, Babak Razani, Kenneth B. Margulies, Mahmoud Abdellatif, Simon Sedej, Ali Javaheri, Douglas F. Covey, Kartik Mani, Abhinav Diwan</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/15?content=articles&page=2">2</a></li> <li><a href="/tags/15?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/15?content=articles&page=47">47</a></li> <li><a href="/tags/15?content=articles&page=48">48</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/15?content=articles&page=2">Next →</a></li></ul></div> </div> </div> </div> <div class='content ' id='posts'> <div class='row'> <div class='small-12 columns'> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/490">Calpain-6 mediates atherogenic macrophage function</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/490"><div class='article-metadata'> In this episode, Takuro Miyazaki and colleagues reveal that elevation of calpain-6 in macrophages promotes atherogenic functions by disrupting CWC22/EJC/Rac1 signaling. <br> <span class='published-at smaller'> Published August 15, 2016 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/107"><span style='margin-right: 6px' class="label-article-type">Video Abstracts</span></a><a href="/tags/15"><span style='margin-right: 6px' class="label-specialty">Cardiology</span></a> </div> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/313">Kruppel-like factor 4 keeps the heart healthy</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/313"><div class='article-metadata'> Xudong Liao and colleagues identify KLF4 as an important regulator of mitochondrial development and function in the heart… <br> <span class='published-at smaller'> Published August 4, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/15"><span style='margin-right: 6px' class="label-specialty">Cardiology</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/313"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/384/thumb_SSS_79964.jpg" /></a> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/288">Oxidation impedes cardioprotection</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/288"><div class='article-metadata'> Taishi Nakamura and colleagues reveal that oxidation prevents the beneficial effects of PKG1α in response to cardiac stress… <br> <span class='published-at smaller'> Published May 4, 2015 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/15"><span style='margin-right: 6px' class="label-specialty">Cardiology</span></a> </div> </div> </div> <div class='large-4 columns'> <a href="/posts/288"><img width="100" src="//dm5migu4zj3pb.cloudfront.net/posts/file/365/thumb_80275_SSS.jpg" /></a> </div> </div> </div> </div> <div class='row'> <div class='small-12 columns'> </div> </div> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; 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