Sam Simmonds, Jan D. Huizinga, Andrew J. Taberner, Peng Du, Timothy R. Angeli-Gordon
The gastroduodenal junction is uniquely capable of regulating digestive functions in the gastrointestinal system. The pyloric sphincter, which demarcates the stomach from the small intestine, acts as a mechanical and electrical barrier, isolating each organ, thus enabling independent behaviors that are critical for proper digestion. Unique electrical patterns in the stomach, pylorus, and duodenum underpin the distinct contractile patterns of these regions, and improper organization of these mechanical behaviors leads to clinical conditions such as gastroparesis and dumping syndrome. For this reason, the gastroduodenal junction should be a focal point in investigations of novel biomarkers of gastrointestinal dysfunction. This review summarizes the current knowledge of bioelectrical and mechanical characteristics of the gastroduodenal junction, as well as the relevant underlying anatomy. As there is limited documentation of physiological recordings from the gastroduodenal junction of humans, inferences are made from animal studies and from measurements taken from other regions of the gastrointestinal tract, where appropriate. We suggest hypotheses on gastroduodenal electromechanical coupling and propose further studies to support or reject these ideas. Improved physiological understanding of this region, and the advent of novel diagnostic and therapeutic tools are crucial aspects for the future of clinical gastrointestinal medicine.
{"title":"Electromechanical coupling across the gastroduodenal junction","authors":"Sam Simmonds, Jan D. Huizinga, Andrew J. Taberner, Peng Du, Timothy R. Angeli-Gordon","doi":"10.1111/apha.70008","DOIUrl":"https://doi.org/10.1111/apha.70008","url":null,"abstract":"<p>The gastroduodenal junction is uniquely capable of regulating digestive functions in the gastrointestinal system. The pyloric sphincter, which demarcates the stomach from the small intestine, acts as a mechanical and electrical barrier, isolating each organ, thus enabling independent behaviors that are critical for proper digestion. Unique electrical patterns in the stomach, pylorus, and duodenum underpin the distinct contractile patterns of these regions, and improper organization of these mechanical behaviors leads to clinical conditions such as gastroparesis and dumping syndrome. For this reason, the gastroduodenal junction should be a focal point in investigations of novel biomarkers of gastrointestinal dysfunction. This review summarizes the current knowledge of bioelectrical and mechanical characteristics of the gastroduodenal junction, as well as the relevant underlying anatomy. As there is limited documentation of physiological recordings from the gastroduodenal junction of humans, inferences are made from animal studies and from measurements taken from other regions of the gastrointestinal tract, where appropriate. We suggest hypotheses on gastroduodenal electromechanical coupling and propose further studies to support or reject these ideas. Improved physiological understanding of this region, and the advent of novel diagnostic and therapeutic tools are crucial aspects for the future of clinical gastrointestinal medicine.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdullah Kaplan, Lana El-Samadi, Rana Zahreddine, Ghadir Amin, George W. Booz, Fouad A. Zouein
G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.
{"title":"Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure","authors":"Abdullah Kaplan, Lana El-Samadi, Rana Zahreddine, Ghadir Amin, George W. Booz, Fouad A. Zouein","doi":"10.1111/apha.70010","DOIUrl":"https://doi.org/10.1111/apha.70010","url":null,"abstract":"<p>G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Psoriasis vulgaris has established associations with psychiatric conditions such as depression, anxiety, and chronic stress. This review aims to evaluate current theories and evidence regarding the role of proinflammatory cytokines and neuropeptides in connecting systemic inflammation, psychological stress, and inflammatory skin diseases, namely psoriasis. A literature review was conducted to analyze studies that explore the connections between psoriasis, psychiatric conditions, and biological mediators, including inflammatory cytokines [interferon (IFN)-γ, interleukin (IL)-1, IL-2, IL-6, IL-12, tumor necrosis factor (TNF)-α, IL-22, IL-17], neuropeptides [calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP)], as well as the hypothalamic–pituitary–adrenal (HPA) axis. Existing literature indicates that psychiatric state can influence cutaneous conditions through immune, neural, and endocrine mediators. The elevated rates of anxiety and depression observed in psoriasis patients are likely due to both the inflammatory process itself and the chronic stress associated with disease management, highlighting the importance of managing stress, and addressing mental health to improve clinical outcomes. While the literature suggests proinflammatory cytokines and neuropeptides may be key links between systemic inflammation, psoriasis, and psychiatric comorbidities, further research is necessary to continue to elucidate physiological mechanisms and explore the potential for new treatment modalities.
{"title":"Proinflammatory cytokines and neuropeptides in psoriasis, depression, and anxiety","authors":"Emily L. Keenan, Richard D. Granstein","doi":"10.1111/apha.70019","DOIUrl":"https://doi.org/10.1111/apha.70019","url":null,"abstract":"<p>Psoriasis vulgaris has established associations with psychiatric conditions such as depression, anxiety, and chronic stress. This review aims to evaluate current theories and evidence regarding the role of proinflammatory cytokines and neuropeptides in connecting systemic inflammation, psychological stress, and inflammatory skin diseases, namely psoriasis. A literature review was conducted to analyze studies that explore the connections between psoriasis, psychiatric conditions, and biological mediators, including inflammatory cytokines [interferon (IFN)-γ, interleukin (IL)-1, IL-2, IL-6, IL-12, tumor necrosis factor (TNF)-α, IL-22, IL-17], neuropeptides [calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP)], as well as the hypothalamic–pituitary–adrenal (HPA) axis. Existing literature indicates that psychiatric state can influence cutaneous conditions through immune, neural, and endocrine mediators. The elevated rates of anxiety and depression observed in psoriasis patients are likely due to both the inflammatory process itself and the chronic stress associated with disease management, highlighting the importance of managing stress, and addressing mental health to improve clinical outcomes. While the literature suggests proinflammatory cytokines and neuropeptides may be key links between systemic inflammation, psoriasis, and psychiatric comorbidities, further research is necessary to continue to elucidate physiological mechanisms and explore the potential for new treatment modalities.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>The tight junction (TJ) is a specialized region of cell-to-cell contact located at the most apical aspect of the junctional complex of epithelial or endothelial cells. Forming a continuous belt-like structure, TJs play an important role in establishing cellular barriers to the external environment and selectively regulating the paracellular permeability of solutes, electrolytes, and water. TJs are composed of intracellular and transmembrane proteins. The claudins are a transmembrane family of TJ proteins, interacting both within the same cell and between adjacent cells. Claudins form either pores or barriers across the paracellular space, and their unique composition regulates the permeability of the shunt. In this issue of <i>Acta Physiologica</i>, Pouyiourou et al.<span><sup>1</sup></span> shed new light on the role of claudins expressed in the kidney.</p><p>The kidney is critical for electrolyte and water balance as it amends their urinary excretion to maintain electrolyte composition, osmolality, and blood pressure. Transport along the renal tubule depends on both the paracellular and transcellular movement of electrolytes. In the proximal tubule, paracellular reabsorption of cations occurs via CLDN2 and CLND12,<span><sup>2</sup></span> while anions permeate this segment via CDLN10a.<span><sup>3</sup></span> In the thick ascending limb, the paracellular shunt is cation-selective, with CLDN10b appearing to form pores preferentially permeable to monovalent cations, while pores formed by CLDN16 and CLDN19 are preferentially permeable to divalent cations. Notably, CLDN14 is highly regulated by the calcium-sensing receptor, and when plasma calcium levels increase, CLDN14 expression increases markedly contributing to a paracellular barrier to this segment.<span><sup>4</sup></span> The distal nephron is a tighter epithelium than the proximal tubule and thick ascending limb. However, it exhibits some anion-selective permeability, potentially mediated by CLDN4 and CLDN8, although conflicting evidence exists regarding their contribution. CLDN3 and CLDN7 are expressed in the distal nephron and likely contribute to the barrier properties of these epithelia.</p><p>Overexpression of individual claudins in cell culture has produced variable effects on ion permeability. These variations are likely due to the cell line used, and a result of interactions with endogenous claudins or changes in the expression of endogenous claudins.<span><sup>5</sup></span> Consistent with this, overexpression of CLDN4 in the OK proximal tubule model increases transepithelial resistance but also upregulates the expression of endogenous <i>CLDN1</i>, <i>CLDN6</i>, and <i>CLDN9</i>.<span><sup>6</sup></span> As discussed previously,<span><sup>5</sup></span> when overexpressed in LLC-PK1 cells, CLDN16 increases sodium permeability with only moderate effects on magnesium permeability. However, humans with pathogenic mutations in <i>CLDN16</i> display hypomagnesemia with hypercalci
{"title":"A reductionist approach to studying renal claudins provides insights into tubular permeability properties","authors":"R. Todd Alexander, Henrik Dimke","doi":"10.1111/apha.70014","DOIUrl":"https://doi.org/10.1111/apha.70014","url":null,"abstract":"<p>The tight junction (TJ) is a specialized region of cell-to-cell contact located at the most apical aspect of the junctional complex of epithelial or endothelial cells. Forming a continuous belt-like structure, TJs play an important role in establishing cellular barriers to the external environment and selectively regulating the paracellular permeability of solutes, electrolytes, and water. TJs are composed of intracellular and transmembrane proteins. The claudins are a transmembrane family of TJ proteins, interacting both within the same cell and between adjacent cells. Claudins form either pores or barriers across the paracellular space, and their unique composition regulates the permeability of the shunt. In this issue of <i>Acta Physiologica</i>, Pouyiourou et al.<span><sup>1</sup></span> shed new light on the role of claudins expressed in the kidney.</p><p>The kidney is critical for electrolyte and water balance as it amends their urinary excretion to maintain electrolyte composition, osmolality, and blood pressure. Transport along the renal tubule depends on both the paracellular and transcellular movement of electrolytes. In the proximal tubule, paracellular reabsorption of cations occurs via CLDN2 and CLND12,<span><sup>2</sup></span> while anions permeate this segment via CDLN10a.<span><sup>3</sup></span> In the thick ascending limb, the paracellular shunt is cation-selective, with CLDN10b appearing to form pores preferentially permeable to monovalent cations, while pores formed by CLDN16 and CLDN19 are preferentially permeable to divalent cations. Notably, CLDN14 is highly regulated by the calcium-sensing receptor, and when plasma calcium levels increase, CLDN14 expression increases markedly contributing to a paracellular barrier to this segment.<span><sup>4</sup></span> The distal nephron is a tighter epithelium than the proximal tubule and thick ascending limb. However, it exhibits some anion-selective permeability, potentially mediated by CLDN4 and CLDN8, although conflicting evidence exists regarding their contribution. CLDN3 and CLDN7 are expressed in the distal nephron and likely contribute to the barrier properties of these epithelia.</p><p>Overexpression of individual claudins in cell culture has produced variable effects on ion permeability. These variations are likely due to the cell line used, and a result of interactions with endogenous claudins or changes in the expression of endogenous claudins.<span><sup>5</sup></span> Consistent with this, overexpression of CLDN4 in the OK proximal tubule model increases transepithelial resistance but also upregulates the expression of endogenous <i>CLDN1</i>, <i>CLDN6</i>, and <i>CLDN9</i>.<span><sup>6</sup></span> As discussed previously,<span><sup>5</sup></span> when overexpressed in LLC-PK1 cells, CLDN16 increases sodium permeability with only moderate effects on magnesium permeability. However, humans with pathogenic mutations in <i>CLDN16</i> display hypomagnesemia with hypercalci","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gijs A. C. Franken, Willem Bosman, Hyun Jun Jung, Caro Bos, Femke Latta, Mark Knepper, Joost G. J. Hoenderop, Jeroen H. F. de Baaij
Background
The distal convoluted tubule (DCT) plays an indispensable role in magnesium (Mg2+) reabsorption in the kidney. Yet, the extrusion mechanism of Mg2+ has not been identified. The solute carrier 41A3 (SLC41A3) has been suggested to be involved in Mg2+ extrusion, but this has never been conclusively demonstrated.
Methods
Using available RNA-sequencing data and real-time quantitative PCR, expression of two alternative Slc41a3 transcripts, encoding isoform (Iso) 1 or 2, were assessed in kidney and isolated DCT tubules. HEK293 or HAP1 cells were transfected with plasmids expressing either of the isoforms, followed by 25Mg2+ transport studies. Identification of cis-regulatory elements (CRE) was achieved by combining data from publicly available ATAC sequencing data and luciferase assays.
Results
Gene expression studies revealed a distinct transcript of Slc41a3 in the DCT with an alternative promoter, leading to a protein with a unique N-terminus; SLC41A3-Iso 2. HEK293 cells overexpressing SLC41A3-Iso 2, but not -Iso 1, exhibited 2.7-fold and 1.6-fold higher 25Mg2+ uptake and extrusion, compared to mock, respectively. The transport was independent of Na+, of the Mg2+ channel TRPM7 or of transporters CNNM3 and -4. We identified a CRE accessible in the DCT, ±2.8kb upstream of the transcript. The presence of the CRE increased the Slc41a3-Iso 2 promoter activity 3.8-fold following luciferase assays, indicating the CRE contains an enhancer function.
Conclusion
In conclusion, we identified two alternative transcripts of Slc41a3 in mouse. Slc41a3-Iso 2 is enriched within the DCT using specific gene regulatory elements. We speculate that specifically in the DCT, SLC41A3-Iso 2 orchestrates Mg2+ extrusion.
{"title":"A distal convoluted tubule-specific isoform of murine SLC41A3 extrudes magnesium","authors":"Gijs A. C. Franken, Willem Bosman, Hyun Jun Jung, Caro Bos, Femke Latta, Mark Knepper, Joost G. J. Hoenderop, Jeroen H. F. de Baaij","doi":"10.1111/apha.70018","DOIUrl":"https://doi.org/10.1111/apha.70018","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The distal convoluted tubule (DCT) plays an indispensable role in magnesium (Mg<sup>2+</sup>) reabsorption in the kidney. Yet, the extrusion mechanism of Mg<sup>2+</sup> has not been identified. The solute carrier 41A3 (SLC41A3) has been suggested to be involved in Mg<sup>2+</sup> extrusion, but this has never been conclusively demonstrated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using available RNA-sequencing data and real-time quantitative PCR, expression of two alternative <i>Slc41a3</i> transcripts, encoding isoform (Iso) 1 or 2, were assessed in kidney and isolated DCT tubules. HEK293 or HAP1 cells were transfected with plasmids expressing either of the isoforms, followed by <sup>25</sup>Mg<sup>2+</sup> transport studies. Identification of cis-regulatory elements (CRE) was achieved by combining data from publicly available ATAC sequencing data and luciferase assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Gene expression studies revealed a distinct transcript of <i>Slc41a3</i> in the DCT with an alternative promoter, leading to a protein with a unique N-terminus; SLC41A3-Iso 2. HEK293 cells overexpressing SLC41A3-Iso 2, but not -Iso 1, exhibited 2.7-fold and 1.6-fold higher <sup>25</sup>Mg<sup>2+</sup> uptake and extrusion, compared to mock, respectively. The transport was independent of Na<sup>+</sup>, of the Mg<sup>2+</sup> channel TRPM7 or of transporters CNNM3 and -4. We identified a CRE accessible in the DCT, ±2.8kb upstream of the transcript. The presence of the CRE increased the <i>Slc41a3-Iso 2</i> promoter activity 3.8-fold following luciferase assays, indicating the CRE contains an enhancer function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, we identified two alternative transcripts of <i>Slc41a3</i> in mouse. <i>Slc41a3-Iso 2</i> is enriched within the DCT using specific gene regulatory elements. We speculate that specifically in the DCT, SLC41A3-Iso 2 orchestrates Mg<sup>2+</sup> extrusion.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathalia Senger, Gislane de Almeida-Santos, Gabriela Cavazza Cerri, Joice Silva Mota, Aline Cristina Parletta, Denival Nascimento Vieira-Junior, Joaquim Teixeira Xavier Junior, Rogério Silva do Nascimento, Danilo Chaves da Silva Ramos de Souza, Maria Claudia Costa Irigoyen, Gabriela Placoná Diniz, José Maria Alvarez Mosig, Tim Christian Kuhn, Florian Leuschner, Maria Regina D'Império Lima, Maria Luiza Morais Barreto-Chaves
Aims
The heart is one of the main targets of thyroid hormone. Patients with hyperthyroidism, a disease with high incidence in the population, have increased arrhythmia risk and cardiac hypertrophy, which is an independent predictor of adverse cardiovascular outcomes. Recent research has revealed the essential roles of leukocytes in cardiac homeostasis and stress-induced responses. Here, we aimed to evaluate the role of immune cells in cardiac changes induced by elevated triiodothyronine (T3) levels.
Methods
The hyperthyroid condition in mice was mimicked by daily injections (i.p.) of T3 (14 μg/100 g BW) for 7 or 14 days.
Results
Increased heart rate and cardiac mass observed after 7 days of T3 treatment was associated with enhanced myocardial population of neutrophils, dendritic cells, and inflammatory phenotypes of monocytes and macrophages, without circulating changes in these cells, as evaluated by flow cytometry. In vitro experiments demonstrated bias toward pro-inflammatory polarization in isolated bone marrow-derived macrophages (BMDM) in response to T3. Interestingly, depletion of macrophages in mice prevented hypertrophic heart growth, tachycardia, and increased gene expression of the pro-inflammatory cytokine interleukin-(IL)-6 caused by hyperthyroid condition.
Conclusion
Together, these new findings indicate the involvement of macrophages in the cardiac changes promoted by higher T3 levels. Considering that sustained cardiac growth and tachycardia can potentially lead to heart failure, our results suggest that targeting macrophages might be a novel therapeutic approach for attenuating cardiac disorders caused by hyperthyroidism.
{"title":"Increased macrophages contribute to thyroid hormone-induced cardiac alterations in mice","authors":"Nathalia Senger, Gislane de Almeida-Santos, Gabriela Cavazza Cerri, Joice Silva Mota, Aline Cristina Parletta, Denival Nascimento Vieira-Junior, Joaquim Teixeira Xavier Junior, Rogério Silva do Nascimento, Danilo Chaves da Silva Ramos de Souza, Maria Claudia Costa Irigoyen, Gabriela Placoná Diniz, José Maria Alvarez Mosig, Tim Christian Kuhn, Florian Leuschner, Maria Regina D'Império Lima, Maria Luiza Morais Barreto-Chaves","doi":"10.1111/apha.70011","DOIUrl":"https://doi.org/10.1111/apha.70011","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>The heart is one of the main targets of thyroid hormone. Patients with hyperthyroidism, a disease with high incidence in the population, have increased arrhythmia risk and cardiac hypertrophy, which is an independent predictor of adverse cardiovascular outcomes. Recent research has revealed the essential roles of leukocytes in cardiac homeostasis and stress-induced responses. Here, we aimed to evaluate the role of immune cells in cardiac changes induced by elevated triiodothyronine (T3) levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The hyperthyroid condition in mice was mimicked by daily injections (i.p.) of T3 (14 μg/100 g BW) for 7 or 14 days.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Increased heart rate and cardiac mass observed after 7 days of T3 treatment was associated with enhanced myocardial population of neutrophils, dendritic cells, and inflammatory phenotypes of monocytes and macrophages, without circulating changes in these cells, as evaluated by flow cytometry. In vitro experiments demonstrated bias toward pro-inflammatory polarization in isolated bone marrow-derived macrophages (BMDM) in response to T3. Interestingly, depletion of macrophages in mice prevented hypertrophic heart growth, tachycardia, and increased gene expression of the pro-inflammatory cytokine interleukin-(IL)-6 caused by hyperthyroid condition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Together, these new findings indicate the involvement of macrophages in the cardiac changes promoted by higher T3 levels. Considering that sustained cardiac growth and tachycardia can potentially lead to heart failure, our results suggest that targeting macrophages might be a novel therapeutic approach for attenuating cardiac disorders caused by hyperthyroidism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>In a recent issue of <i>Acta Physiologica</i>, Kulow et al. (2025) propose that the enzyme 2,3-Bisphosphoglycerate mutase (BPGM) is involved in the pathophysiology of acute kidney injury. BPGM is well known for the production of 2,3-Bisphsophoglycerate (2,3-BPG) in erythrocytes, where 2,3-BPG exerts crucial modulation of the affinity by which hemoglobin binds oxygen and hence shifts the O<sub>2</sub> equilibrium curve to the right. Kulow et al. (2025) now reveal that this legendary enzyme is expressed in the distal parts of the nephron in the kidney.<span><sup>1</sup></span></p><p>Recent advances in proteomics and transcriptomics enable to establish correlations of gene or protein expression of a huge variety of products, and oftentimes identify products that would not have been in focus with more traditional approaches. Correlations, however, do not establish causality, and finding a physiological “home” of these newly found products often involves dedicated and laborious efforts; This is exactly what Kulow et al. (2025) do in their recent study in <i>Acta Physiologica</i>.</p><p>In 2013, the same research group at Charite showed that BPGM is upregulated acute kidney injury in mice<span><sup>2</sup></span> and Kulow et al.<span><sup>1</sup></span> therefore developed an inducible kidney-specific knockout mouse model to understand the physiological ramifications of this surprising finding. These mice consistently developed signs of acute injury within days after knock-out induction. So, now there is information about increased expression of BGPM during disease and evident disease development in case of lack of expression. The latter indicates a bona fide physiological function of BGPM, which goes missing after knockout.</p><p>Most of the known functions of BGPM and 2,3-BGP production stem from mammalian erythrocytes. These nuclei- and mitochondria-free hemoglobin/O<sub>2</sub> transporters rely on anaerobic glycolysis for their entire metabolic needs. In a sideline—but regulatory—metabolic pathway, BGPM produces 2,3-BGP during the process of glucose metabolism. As recently reviewed in Acta Physiologica, the understanding of erythrocyte metabolism also got a substantial boost by new “-omics” findings in the recent years.<span><sup>3</sup></span> BGPM expression and 2,3-BGP production have also been described beyond erythrocytes, such as placenta<span><sup>4</sup></span> and astrocytes.<span><sup>5</sup></span> The placental expression is perhaps the easiest to understand in analogy as also here O<sub>2</sub> release between compartments has to be regulated. In the case of erythrocytes, the unloading of oxygen to the needy tissues (Figure 1), in this case of the placenta the transfer of oxygen from maternal to fetal hemoglobin. There are of course no direct oxygen-hemoglobin interactions in astrocytes, but their metabolism subserves neuronal cells. In analogy to these examples, one can speculate that BPGM expression serves in specialized sensor
{"title":"2,3-Bisphosphoglycerate mutase (BPGM) and kidney—Potential new role in the coordination of metabolic needs of renal epithelia","authors":"Nina Himmerkus, Tobias Wang","doi":"10.1111/apha.70013","DOIUrl":"https://doi.org/10.1111/apha.70013","url":null,"abstract":"<p>In a recent issue of <i>Acta Physiologica</i>, Kulow et al. (2025) propose that the enzyme 2,3-Bisphosphoglycerate mutase (BPGM) is involved in the pathophysiology of acute kidney injury. BPGM is well known for the production of 2,3-Bisphsophoglycerate (2,3-BPG) in erythrocytes, where 2,3-BPG exerts crucial modulation of the affinity by which hemoglobin binds oxygen and hence shifts the O<sub>2</sub> equilibrium curve to the right. Kulow et al. (2025) now reveal that this legendary enzyme is expressed in the distal parts of the nephron in the kidney.<span><sup>1</sup></span></p><p>Recent advances in proteomics and transcriptomics enable to establish correlations of gene or protein expression of a huge variety of products, and oftentimes identify products that would not have been in focus with more traditional approaches. Correlations, however, do not establish causality, and finding a physiological “home” of these newly found products often involves dedicated and laborious efforts; This is exactly what Kulow et al. (2025) do in their recent study in <i>Acta Physiologica</i>.</p><p>In 2013, the same research group at Charite showed that BPGM is upregulated acute kidney injury in mice<span><sup>2</sup></span> and Kulow et al.<span><sup>1</sup></span> therefore developed an inducible kidney-specific knockout mouse model to understand the physiological ramifications of this surprising finding. These mice consistently developed signs of acute injury within days after knock-out induction. So, now there is information about increased expression of BGPM during disease and evident disease development in case of lack of expression. The latter indicates a bona fide physiological function of BGPM, which goes missing after knockout.</p><p>Most of the known functions of BGPM and 2,3-BGP production stem from mammalian erythrocytes. These nuclei- and mitochondria-free hemoglobin/O<sub>2</sub> transporters rely on anaerobic glycolysis for their entire metabolic needs. In a sideline—but regulatory—metabolic pathway, BGPM produces 2,3-BGP during the process of glucose metabolism. As recently reviewed in Acta Physiologica, the understanding of erythrocyte metabolism also got a substantial boost by new “-omics” findings in the recent years.<span><sup>3</sup></span> BGPM expression and 2,3-BGP production have also been described beyond erythrocytes, such as placenta<span><sup>4</sup></span> and astrocytes.<span><sup>5</sup></span> The placental expression is perhaps the easiest to understand in analogy as also here O<sub>2</sub> release between compartments has to be regulated. In the case of erythrocytes, the unloading of oxygen to the needy tissues (Figure 1), in this case of the placenta the transfer of oxygen from maternal to fetal hemoglobin. There are of course no direct oxygen-hemoglobin interactions in astrocytes, but their metabolism subserves neuronal cells. In analogy to these examples, one can speculate that BPGM expression serves in specialized sensor ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefanos Volianitis, Chie Yoshiga, Thomas Vogelsang, Niels H. Secher
<p>Older people develop an exaggerated blood pressure (BP) during whole body exercise, which is associated with a higher risk of sudden cardiac death, myocardial infarction, future hypertension, cardiovascular disease, and left ventricular hypertrophy.<span><sup>1</sup></span> Since regular exercise is a common mitigating strategy for many health pathologies associated with aging, identification of the underlying mechanisms responsible for the exaggerated BP response is warranted in order to establish effective exercise prescription.</p><p>Blood pressure, both at rest and exercise, is regulated within a narrow range around a set value (operating point, OP) by the arterial baroreflex (ABR) via modulation of autonomic neural activity to the heart and vasculature.<span><sup>2</sup></span> As BP increases during exercise, the ABR is reset in direct relation to the exercise intensity, and regulates the elevated BP around the new OP.<span><sup>2</sup></span> The resetting of the ABR during exercise is mediated by activation and interaction of central and peripheral signals arising from higher brain centers (central command), exercising skeletal muscles (exercise pressor reflex) and the cardiopulmonary baroreceptors.<span><sup>3, 4</sup></span></p><p>In young healthy adults, loading of the cardiopulmonary baroreceptors during dynamic exercise inhibits the ABR resetting and lowers the prevailing BP during exercise,<span><sup>3, 4</sup></span> presumably by providing a strong inhibitory influence on the muscle sympathetic nerve activity (MSNA). Considering that the interaction between cardiopulmonary baroreceptors and ABR is attenuated with aging,<span><sup>5</sup></span> it is plausible that the exaggerated BP response to exercise in the elderly is due to an impaired cardiopulmonary baroreflex, such that attenuated inhibition of MSNA fails to adequately reset the ABR to a lower BP.</p><p>The effect of aging on the attenuating influence of the cardiopulmonary baroreceptors on the ABR resetting during exercise was evaluated by comparing the carotid-vasomotor baroreflex function curve in young (24 ± 1 years; <i>n</i> = 12) and older (71 ± 2 years; <i>n</i> = 12) healthy normotensive adults during upright and supine sub-maximal cycling that aimed to increase central blood volume, and thus load the cardiopulmonary baroreceptors. Both age groups, who were recreationally physically active 2–3 times per week but not systematically training, non-smokers and free from current medical symptoms, medication and history of major disease, signed informed consent to participate in accordance with the Declaration of Helsinki and was approved by the Copenhagen ethics committee (KF 01-186/02).</p><p>All subjects were familiarized with the experimental procedures, and abstained from eating for 2 h, caffeinated beverages for 12 h, and strenuous physical activity and alcohol for at least 24 h prior to the experimental session. Heart rate, BP and oxygen uptake (V̇O<sub>2</sub>
{"title":"Did you know? Aging does not compromise the inhibitory influence of the cardiopulmonary baroreceptors on blood pressure during exercise","authors":"Stefanos Volianitis, Chie Yoshiga, Thomas Vogelsang, Niels H. Secher","doi":"10.1111/apha.70015","DOIUrl":"https://doi.org/10.1111/apha.70015","url":null,"abstract":"<p>Older people develop an exaggerated blood pressure (BP) during whole body exercise, which is associated with a higher risk of sudden cardiac death, myocardial infarction, future hypertension, cardiovascular disease, and left ventricular hypertrophy.<span><sup>1</sup></span> Since regular exercise is a common mitigating strategy for many health pathologies associated with aging, identification of the underlying mechanisms responsible for the exaggerated BP response is warranted in order to establish effective exercise prescription.</p><p>Blood pressure, both at rest and exercise, is regulated within a narrow range around a set value (operating point, OP) by the arterial baroreflex (ABR) via modulation of autonomic neural activity to the heart and vasculature.<span><sup>2</sup></span> As BP increases during exercise, the ABR is reset in direct relation to the exercise intensity, and regulates the elevated BP around the new OP.<span><sup>2</sup></span> The resetting of the ABR during exercise is mediated by activation and interaction of central and peripheral signals arising from higher brain centers (central command), exercising skeletal muscles (exercise pressor reflex) and the cardiopulmonary baroreceptors.<span><sup>3, 4</sup></span></p><p>In young healthy adults, loading of the cardiopulmonary baroreceptors during dynamic exercise inhibits the ABR resetting and lowers the prevailing BP during exercise,<span><sup>3, 4</sup></span> presumably by providing a strong inhibitory influence on the muscle sympathetic nerve activity (MSNA). Considering that the interaction between cardiopulmonary baroreceptors and ABR is attenuated with aging,<span><sup>5</sup></span> it is plausible that the exaggerated BP response to exercise in the elderly is due to an impaired cardiopulmonary baroreflex, such that attenuated inhibition of MSNA fails to adequately reset the ABR to a lower BP.</p><p>The effect of aging on the attenuating influence of the cardiopulmonary baroreceptors on the ABR resetting during exercise was evaluated by comparing the carotid-vasomotor baroreflex function curve in young (24 ± 1 years; <i>n</i> = 12) and older (71 ± 2 years; <i>n</i> = 12) healthy normotensive adults during upright and supine sub-maximal cycling that aimed to increase central blood volume, and thus load the cardiopulmonary baroreceptors. Both age groups, who were recreationally physically active 2–3 times per week but not systematically training, non-smokers and free from current medical symptoms, medication and history of major disease, signed informed consent to participate in accordance with the Declaration of Helsinki and was approved by the Copenhagen ethics committee (KF 01-186/02).</p><p>All subjects were familiarized with the experimental procedures, and abstained from eating for 2 h, caffeinated beverages for 12 h, and strenuous physical activity and alcohol for at least 24 h prior to the experimental session. Heart rate, BP and oxygen uptake (V̇O<sub>2</sub>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Striatin (Strn) is an important scaffolding protein linked to various cardiovascular diseases, including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy, as demonstrated in preclinical<span><sup>1-3</sup></span> studies. The use of cardiomyocytes derived from embryonic stem cells and induced pluripotent stem cells has become increasingly valuable for studying the molecular pathomechanisms underlying these cardiomyopathies. These models closely resemble human cardiomyocytes and possess the ability to differentiate into various cell<span><sup>4-9</sup></span> types, providing a robust platform for preclinical studies and drug screening. Despite their inherent limitations, such as the lack of hormonal or neural support, these models have successfully elucidated several channelopathies and cardiomyopathies.<span><sup>4-11</sup></span></p><p>Strn is characterized by four distinct protein–protein interaction domains, yet its functional role in cardiomyocytes remains inadequately explored. Notably, the specific impact of Strn on ion channel currents within cardiomyocytes has not been investigated until now. The study by Benzoni et al.<span><sup>12</sup></span> provides the first evidence of Strn's functional significance through a knockout model in cardiomyocytes derived from embryoid bodies. The authors observe critical dysregulation in contraction dynamics and intracellular calcium handling, alongside a higher beating rate and alterations in action potential characteristics. Their findings reveal increased densities of both transient and late sodium channel currents in the Strn knockout model. Furthermore, the authors analyze INCX activity, noting a reduction in the knockout model compared to wild-type cardiomyocytes, which suggests a potential interplay between sodium channel currents and calcium homeostasis.</p><p>Benzoni et al. propose that these observed alterations stem from a dysregulated cytoskeletal network and ion channel function due to the absence of Strn. Intriguingly, the study also explores the effects of taxol, a significant inhibitor of the late sodium current, which reverses the observed changes in the knockout model. This finding underscores the multifaceted role of Strn in not only mediating functional changes in heart muscle but also modulating broader aspects of cellular physiology.</p><p>Previous studies have indicated that cardiac Strn interacts with caveolin-3 and calmodulin in a calcium-sensitive manner, which regulates the spontaneous contraction<span><sup>13</sup></span> rate of cardiomyocytes (Figure 1). Additionally, genome-wide association studies have linked the localization of Strn to changes in QRS duration, suggesting its potential involvement in heart rhythm disorders and sudden cardiac death.<span><sup>14</sup></span> However, comprehensive studies involving larger patient cohorts are necessary to fully elucidate the role of Strn in these pathologies.</p><p
{"title":"Striatin protein's role in human cardiomyocytes: Connection to electrical dysregulation and sudden cardiac death","authors":"Ibrahim El-Battrawy, Nazha Hamdani, Ibrahim Akin","doi":"10.1111/apha.70009","DOIUrl":"10.1111/apha.70009","url":null,"abstract":"<p>Striatin (Strn) is an important scaffolding protein linked to various cardiovascular diseases, including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy, as demonstrated in preclinical<span><sup>1-3</sup></span> studies. The use of cardiomyocytes derived from embryonic stem cells and induced pluripotent stem cells has become increasingly valuable for studying the molecular pathomechanisms underlying these cardiomyopathies. These models closely resemble human cardiomyocytes and possess the ability to differentiate into various cell<span><sup>4-9</sup></span> types, providing a robust platform for preclinical studies and drug screening. Despite their inherent limitations, such as the lack of hormonal or neural support, these models have successfully elucidated several channelopathies and cardiomyopathies.<span><sup>4-11</sup></span></p><p>Strn is characterized by four distinct protein–protein interaction domains, yet its functional role in cardiomyocytes remains inadequately explored. Notably, the specific impact of Strn on ion channel currents within cardiomyocytes has not been investigated until now. The study by Benzoni et al.<span><sup>12</sup></span> provides the first evidence of Strn's functional significance through a knockout model in cardiomyocytes derived from embryoid bodies. The authors observe critical dysregulation in contraction dynamics and intracellular calcium handling, alongside a higher beating rate and alterations in action potential characteristics. Their findings reveal increased densities of both transient and late sodium channel currents in the Strn knockout model. Furthermore, the authors analyze INCX activity, noting a reduction in the knockout model compared to wild-type cardiomyocytes, which suggests a potential interplay between sodium channel currents and calcium homeostasis.</p><p>Benzoni et al. propose that these observed alterations stem from a dysregulated cytoskeletal network and ion channel function due to the absence of Strn. Intriguingly, the study also explores the effects of taxol, a significant inhibitor of the late sodium current, which reverses the observed changes in the knockout model. This finding underscores the multifaceted role of Strn in not only mediating functional changes in heart muscle but also modulating broader aspects of cellular physiology.</p><p>Previous studies have indicated that cardiac Strn interacts with caveolin-3 and calmodulin in a calcium-sensitive manner, which regulates the spontaneous contraction<span><sup>13</sup></span> rate of cardiomyocytes (Figure 1). Additionally, genome-wide association studies have linked the localization of Strn to changes in QRS duration, suggesting its potential involvement in heart rhythm disorders and sudden cardiac death.<span><sup>14</sup></span> However, comprehensive studies involving larger patient cohorts are necessary to fully elucidate the role of Strn in these pathologies.</p><p","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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