Yu Cui, Lu Yu, Wenqi Cong, Shan Jiang, Xingyu Qiu, Chunchun Wei, Gui Zheng, Jianhua Mao, Ruisheng Liu, Andreas Patzak, Pontus B. Persson, Jianghua Chen, Liang Zhao, En Yin Lai
Aims
A myokine secreted by skeletal muscles during exercise called irisin mitigates ischemia–reperfusion (I/R) injury in epithelial cells of various organs by limiting damage to mitochondria. We test whether irisin may preserve the mitochondrial integrity and function in renal tubular epithelial cells and protect against ischemia–reperfusion-induced acute kidney injury (AKI).
Methods
We correlated serum irisin levels with serum creatinine and BUN levels from both AKI patients and healthy individuals. In mice with irisin administration, various renal injury markers such as serum creatinine, BUN, kidney injury molecule-1 (Kim-1), and neutrophil gelatinase-associated lipocalin (NGAL), and renal histopathology were assessed after I/R. To identify the potential mechanisms of the protective of irisin's protective effect, we perfused proximal tubules under confocal microscopy and analyzed kidney tissues by qPCR, western blot, and immunohistochemistry.
Results
Serum irisin correlated inversely with serum creatinine and BUN levels were significantly lower in AKI patients than in healthy subjects. Administering irisin to mice after I/R decreased biomarker levels for AKI including serum creatinine, BUN, Kim-1, NAGL and lessened histological changes. In kidney tissues of mice, irisin upregulated the mitochondrial autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3), the mitochondrial autophagy pathway-related proteins PTEN-induced putative kinase 1 (PINK1) and Parkinson's disease 2 parkin (PARK2) and downregulated the reactive substrate protein sequestosome 1 (P62) and mitochondrial membrane proteins translocase of outer mitochondrial membrane 20 (TOM20) and translocase of inner mitochondrial membrane 23 (TIM23).
Conclusion
Irisin protects against renal I/R injury, which may involve the preservation of mitochondrial integrity and function.
{"title":"Irisin preserves mitochondrial integrity and function in tubular epithelial cells after ischemia–reperfusion-induced acute kidney injury","authors":"Yu Cui, Lu Yu, Wenqi Cong, Shan Jiang, Xingyu Qiu, Chunchun Wei, Gui Zheng, Jianhua Mao, Ruisheng Liu, Andreas Patzak, Pontus B. Persson, Jianghua Chen, Liang Zhao, En Yin Lai","doi":"10.1111/apha.14211","DOIUrl":"10.1111/apha.14211","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>A myokine secreted by skeletal muscles during exercise called irisin mitigates ischemia–reperfusion (I/R) injury in epithelial cells of various organs by limiting damage to mitochondria. We test whether irisin may preserve the mitochondrial integrity and function in renal tubular epithelial cells and protect against ischemia–reperfusion-induced acute kidney injury (AKI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We correlated serum irisin levels with serum creatinine and BUN levels from both AKI patients and healthy individuals. In mice with irisin administration, various renal injury markers such as serum creatinine, BUN, kidney injury molecule-1 (Kim-1), and neutrophil gelatinase-associated lipocalin (NGAL), and renal histopathology were assessed after I/R. To identify the potential mechanisms of the protective of irisin's protective effect, we perfused proximal tubules under confocal microscopy and analyzed kidney tissues by qPCR, western blot, and immunohistochemistry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Serum irisin correlated inversely with serum creatinine and BUN levels were significantly lower in AKI patients than in healthy subjects. Administering irisin to mice after I/R decreased biomarker levels for AKI including serum creatinine, BUN, Kim-1, NAGL and lessened histological changes. In kidney tissues of mice, irisin upregulated the mitochondrial autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3), the mitochondrial autophagy pathway-related proteins PTEN-induced putative kinase 1 (PINK1) and Parkinson's disease 2 parkin (PARK2) and downregulated the reactive substrate protein sequestosome 1 (P62) and mitochondrial membrane proteins translocase of outer mitochondrial membrane 20 (TOM20) and translocase of inner mitochondrial membrane 23 (TIM23).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Irisin protects against renal I/R injury, which may involve the preservation of mitochondrial integrity and function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786506","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}
Hormones are specific molecules measured in biological fluids by elaborate analytical systems requiring meticulous attention. Variation between laboratories can be expected. However, recently published measurements of AVP, OXT, and BNP in human plasma under basal/control conditions include numbers which, between publications, vary by 100–10 000-fold. Generally, the methods descriptions are scant, at best, and provide no information about quality control measures. Clearly, two results describing the same basal hormone concentration by numbers three orders of magnitude apart are incongruent providing reason for concern. Basal concentrations of bioactive AVP, OXT, and BNP in human plasma are in the order of 1–10 pmol/L. Therefore, assay systems applied to plasma must be able to measure concentrations of less than 1 pmol/L with appropriate specificity and accuracy. Basal concentrations of AVP, OXT, and BNP above 100 pmol/L should be reconsidered, as such results do not reflect bioactive hormone levels in humans, rats, or mice. Any concentration above 1000 pmol/L is of concern because such levels of bioactive hormone may be seen only under extreme conditions, if at all.
{"title":"Plasma concentrations of peptide hormones: Unrealistic levels of vasopressin (AVP), oxytocin (OXT), and brain natriuretic peptide (BNP)","authors":"Peter Bie","doi":"10.1111/apha.14200","DOIUrl":"10.1111/apha.14200","url":null,"abstract":"<p>Hormones are specific molecules measured in biological fluids by elaborate analytical systems requiring meticulous attention. Variation between laboratories can be expected. However, recently published measurements of AVP, OXT, and BNP in human plasma under basal/control conditions include numbers which, between publications, vary by 100–10 000-fold. Generally, the methods descriptions are scant, at best, and provide no information about quality control measures. Clearly, two results describing the same basal hormone concentration by numbers three orders of magnitude apart are incongruent providing reason for concern. Basal concentrations of bioactive AVP, OXT, and BNP in human plasma are in the order of 1–10 pmol/L. Therefore, assay systems applied to plasma must be able to measure concentrations of less than 1 pmol/L with appropriate specificity and accuracy. Basal concentrations of AVP, OXT, and BNP above 100 pmol/L should be reconsidered, as such results do not reflect bioactive hormone levels in humans, rats, or mice. Any concentration above 1000 pmol/L is of concern because such levels of bioactive hormone may be seen only under extreme conditions, if at all.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732905","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}
Till S. Harter, Emma A. Smith, Cristina Salmerón, Angus B. Thies, Bryan Delgado, Rod W. Wilson, Martin Tresguerres
Aim
To identify the physiological role of the acid-base sensing enzyme, soluble adenylyl cyclase (sAC), in red blood cells (RBC) of the model teleost fish, rainbow trout.
Methods
We used: (i) super-resolution microscopy to determine the subcellular location of sAC protein; (ii) live-cell imaging of RBC intracellular pH (pHi) with specific sAC inhibition (KH7 or LRE1) to determine its role in cellular acid-base regulation; (iii) spectrophotometric measurements of haemoglobin–oxygen (Hb-O2) binding in steady-state conditions; and (iv) during simulated arterial-venous transit, to determine the role of sAC in systemic O2 transport.
Results
Distinct pools of sAC protein were detected in the RBC cytoplasm, at the plasma membrane and within the nucleus. Inhibition of sAC decreased the setpoint for RBC pHi regulation by ~0.25 pH units compared to controls, and slowed the rates of RBC pHi recovery after an acid-base disturbance. RBC pHi recovery was entirely through the anion exchanger (AE) that was in part regulated by HCO3−-dependent sAC signaling. Inhibition of sAC decreased Hb-O2 affinity during a respiratory acidosis compared to controls and reduced the cooperativity of O2 binding. During in vitro simulations of arterial-venous transit, sAC inhibition decreased the amount of O2 that is unloaded by ~11%.
Conclusion
sAC represents a novel acid-base sensor in the RBCs of rainbow trout, where it participates in the modulation of RBC pHi and blood O2 transport though the regulation of AE activity. If substantiated in other species, these findings may have broad implications for our understanding of cardiovascular physiology in vertebrates.
{"title":"Soluble adenylyl cyclase is an acid-base sensor in rainbow trout red blood cells that regulates intracellular pH and haemoglobin–oxygen binding","authors":"Till S. Harter, Emma A. Smith, Cristina Salmerón, Angus B. Thies, Bryan Delgado, Rod W. Wilson, Martin Tresguerres","doi":"10.1111/apha.14205","DOIUrl":"10.1111/apha.14205","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To identify the physiological role of the acid-base sensing enzyme, soluble adenylyl cyclase (sAC), in red blood cells (RBC) of the model teleost fish, rainbow trout.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used: (i) super-resolution microscopy to determine the subcellular location of sAC protein; (ii) live-cell imaging of RBC intracellular pH (pH<sub>i</sub>) with specific sAC inhibition (KH7 or LRE1) to determine its role in cellular acid-base regulation; (iii) spectrophotometric measurements of haemoglobin–oxygen (Hb-O<sub>2</sub>) binding in steady-state conditions; and (iv) during simulated arterial-venous transit, to determine the role of sAC in systemic O<sub>2</sub> transport.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Distinct pools of sAC protein were detected in the RBC cytoplasm, at the plasma membrane and within the nucleus. Inhibition of sAC decreased the setpoint for RBC pH<sub>i</sub> regulation by ~0.25 pH units compared to controls, and slowed the rates of RBC pH<sub>i</sub> recovery after an acid-base disturbance. RBC pH<sub>i</sub> recovery was entirely through the anion exchanger (AE) that was in part regulated by HCO<sub>3</sub><sup>−</sup>-dependent sAC signaling. Inhibition of sAC decreased Hb-O<sub>2</sub> affinity during a respiratory acidosis compared to controls and reduced the cooperativity of O<sub>2</sub> binding. During in vitro simulations of arterial-venous transit, sAC inhibition decreased the amount of O<sub>2</sub> that is unloaded by ~11%.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>sAC represents a novel acid-base sensor in the RBCs of rainbow trout, where it participates in the modulation of RBC pH<sub>i</sub> and blood O<sub>2</sub> transport though the regulation of AE activity. If substantiated in other species, these findings may have broad implications for our understanding of cardiovascular physiology in vertebrates.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730786","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}
Francisco Díaz-Castro, Mauro Tuñón-Suárez, Patricia Rivera, Javier Botella, Jorge Cancino, Ana María Figueroa, Juan Gutiérrez, Claudette Cantin, Louise Deldicque, Hermann Zbinden-Foncea, Joachim Nielsen, Carlos Henríquez-Olguín, Eugenia Morselli, Mauricio Castro-Sepúlveda
Aim
The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM).
Methods
Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex-leg). Mitophagy was assessed using protein-related abundance, transmission electron microscopy (TEM), and fluorescence microscopy.
Results
Our results show that acute resistance exercise increased pro-fission protein phosphorylation (DRP1Ser616) and decreased mitophagy markers such as PARKIN and BNIP3L/NIX protein abundance in the Ex-leg. Additionally, mitochondrial complex IV decreased in the Ex-leg when compared to the Rest-leg. In the Ex-leg, TEM and immunofluorescence images showed mitochondrial cristae abnormalities, a mitochondrial fission phenotype, and increased mitophagosome-like structures in both subsarcolemmal and intermyofibrillar mitochondria. We also observed increased mitophagosome-like structures on the subsarcolemmal cleft and mitochondria in the extracellular space of SkM in the Ex-leg. We stimulated human primary myotubes with CCCP, which mimics mitophagy induction in the Ex-leg, and found that BNIP3L/NIX protein abundance decreased independently of lysosomal degradation. Finally, in another human cohort, we found a negative association between BNIP3L/NIX protein abundance with both mitophagosome-like structures and mitochondrial cristae density in the SkM.
Conclusion
The findings suggest that a single bout of resistance exercise can initiate mitophagy, potentially involving mitochondrial ejection, in human skeletal muscle. BNIP3L/NIX is proposed as a sensitive marker for assessing mitophagy flux in SkM.
{"title":"A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle","authors":"Francisco Díaz-Castro, Mauro Tuñón-Suárez, Patricia Rivera, Javier Botella, Jorge Cancino, Ana María Figueroa, Juan Gutiérrez, Claudette Cantin, Louise Deldicque, Hermann Zbinden-Foncea, Joachim Nielsen, Carlos Henríquez-Olguín, Eugenia Morselli, Mauricio Castro-Sepúlveda","doi":"10.1111/apha.14203","DOIUrl":"10.1111/apha.14203","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex-leg). Mitophagy was assessed using protein-related abundance, transmission electron microscopy (TEM), and fluorescence microscopy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our results show that acute resistance exercise increased pro-fission protein phosphorylation (DRP1<sup>Ser616</sup>) and decreased mitophagy markers such as PARKIN and BNIP3L/NIX protein abundance in the Ex-leg. Additionally, mitochondrial complex IV decreased in the Ex-leg when compared to the Rest-leg. In the Ex-leg, TEM and immunofluorescence images showed mitochondrial cristae abnormalities, a mitochondrial fission phenotype, and increased mitophagosome-like structures in both subsarcolemmal and intermyofibrillar mitochondria. We also observed increased mitophagosome-like structures on the subsarcolemmal cleft and mitochondria in the extracellular space of SkM in the Ex-leg. We stimulated human primary myotubes with CCCP, which mimics mitophagy induction in the Ex-leg, and found that BNIP3L/NIX protein abundance decreased independently of lysosomal degradation. Finally, in another human cohort, we found a negative association between BNIP3L/NIX protein abundance with both mitophagosome-like structures and mitochondrial cristae density in the SkM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The findings suggest that a single bout of resistance exercise can initiate mitophagy, potentially involving mitochondrial ejection, in human skeletal muscle. BNIP3L/NIX is proposed as a sensitive marker for assessing mitophagy flux in SkM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632036","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}
Petra Alanova, Lukas Alan, Barbora Opletalova, Romana Bohuslavova, Pavel Abaffy, Katerina Matejkova, Kristyna Holzerova, Daniel Benak, Nina Kaludercic, Roberta Menabo, Fabio Di Lisa, Bohuslav Ostadal, Frantisek Kolar, Gabriela Pavlinkova
Aim
The transcriptional factor HIF-1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF-1α and increase myocardial ischemic tolerance. However, the precise role of HIF-1α in mediating the protective effect remains incompletely understood.
Methods
Male wild-type (WT) mice and mice with partial Hif1a deficiency (hif1a+/−) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA-sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy.
Results
We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a+/− mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3-II/LC3-I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi-1) abolished the infarct size-limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH-induced cardioprotection.
Conclusion
These findings provide new insights into the contribution of HIF-1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway.
{"title":"HIF-1α limits myocardial infarction by promoting mitophagy in mouse hearts adapted to chronic hypoxia","authors":"Petra Alanova, Lukas Alan, Barbora Opletalova, Romana Bohuslavova, Pavel Abaffy, Katerina Matejkova, Kristyna Holzerova, Daniel Benak, Nina Kaludercic, Roberta Menabo, Fabio Di Lisa, Bohuslav Ostadal, Frantisek Kolar, Gabriela Pavlinkova","doi":"10.1111/apha.14202","DOIUrl":"10.1111/apha.14202","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The transcriptional factor HIF-1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF-1α and increase myocardial ischemic tolerance. However, the precise role of HIF-1α in mediating the protective effect remains incompletely understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male wild-type (WT) mice and mice with partial <i>Hif1a</i> deficiency (<i>hif1a</i>\u0000 <sup>+/−</sup>) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA-sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic <i>hif1a</i>\u0000 <sup>+/−</sup> mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3-II/LC3-I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi-1) abolished the infarct size-limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH-induced cardioprotection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings provide new insights into the contribution of HIF-1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625376","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}
Aimi D. K. Hamilton, Laura V. Sparsoe, Mathias Skov, Nanna Johnsen, Mette H. Chreistensen, Thomas J. Corydon, Helle Praetorius
Aim
Urinary tract infections (UTIs) rank among the most prevalent infections in humans, carrying substantial implications for public health. Women experiencing recurrent UTIs are often advised to boost their fluid intake to help eliminate bacteria. In this study, we explored the impact of elevated fluid consumption during UTIs using a mouse model of pyelonephritis.
Methods
UTI was induced in 8–10 w female BALB/cJ-mice by surgically injecting Escherichia coli (O6:K13:H1) into the bladder whereafter mice were randomized to gel food (GF) or regular chow. Immune response and infection severity were determined 24-h post-infection. In vitro bacterial growth (OD600) was determined in urine from mice or from human volunteers.
Results
Gel feeding increased urine output (1.40 ± 0.77 μL min−1, p < 0.01) and diluted the urine (668.7 ± 177 mOsmol kg−1, p < 0.0001) compared to controls on regular chow (urine output: 0.34 ± 0.27 μL min−1, osmolality: 1439 ± 473.5 mOsmol kg−1). Mice on GF had a higher risk of pyelonephritis (87.5%) and more severe infections (26.22 ± 9.88 CFU mg−1 tissue) compared to controls (43.75%; 3.87 ± 3.56 CFU mg−1, p < 0.01). Correspondingly, the growth of E. coli was markedly reduced at osmolalities above 1200 mOsmol kg−1 compared to 600 mOsmol kg−1 and GF mice had lower urine levels of uromodulin (13.70 ± 1.89 μg mL−1, p < 0.01) compared to controls (24.65 ± 2.70 μg mL−1).
Conclusion
Increased water intake and urine flow in mice will markedly increase the risk of pyelonephritis. The increased risk may reflect reduced urine uromodulin combined with optimized growth conditions for E. coli. The study does not immediately support the notion that established UTIs can be eliminated by increased water intake.
{"title":"Increased water intake dilutes protective uromodulin levels in urine and results in increased rates of pyelonephritis in a murine model","authors":"Aimi D. K. Hamilton, Laura V. Sparsoe, Mathias Skov, Nanna Johnsen, Mette H. Chreistensen, Thomas J. Corydon, Helle Praetorius","doi":"10.1111/apha.14204","DOIUrl":"10.1111/apha.14204","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Urinary tract infections (UTIs) rank among the most prevalent infections in humans, carrying substantial implications for public health. Women experiencing recurrent UTIs are often advised to boost their fluid intake to help eliminate bacteria. In this study, we explored the impact of elevated fluid consumption during UTIs using a mouse model of pyelonephritis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>UTI was induced in 8–10 w female BALB/cJ-mice by surgically injecting <i>Escherichia coli</i> (O6:K13:H1) into the bladder whereafter mice were randomized to gel food (GF) or regular chow. Immune response and infection severity were determined 24-h post-infection. In vitro bacterial growth (OD<sub>600</sub>) was determined in urine from mice or from human volunteers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Gel feeding increased urine output (1.40 ± 0.77 μL min<sup>−1</sup>, <i>p</i> < 0.01) and diluted the urine (668.7 ± 177 mOsmol kg<sup>−1</sup>, <i>p</i> < 0.0001) compared to controls on regular chow (urine output: 0.34 ± 0.27 μL min<sup>−1</sup>, osmolality: 1439 ± 473.5 mOsmol kg<sup>−1</sup>). Mice on GF had a higher risk of pyelonephritis (87.5%) and more severe infections (26.22 ± 9.88 CFU mg<sup>−1</sup> tissue) compared to controls (43.75%; 3.87 ± 3.56 CFU mg<sup>−1</sup>, <i>p</i> < 0.01). Correspondingly, the growth <i>of E. coli</i> was markedly reduced at osmolalities above 1200 mOsmol kg<sup>−1</sup> compared to 600 mOsmol kg<sup>−1</sup> and GF mice had lower urine levels of uromodulin (13.70 ± 1.89 μg mL<sup>−1</sup>, <i>p</i> < 0.01) compared to controls (24.65 ± 2.70 μg mL<sup>−1</sup>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Increased water intake and urine flow in mice will markedly increase the risk of pyelonephritis. The increased risk may reflect reduced urine uromodulin combined with optimized growth conditions for <i>E. coli</i>. The study does not immediately support the notion that established UTIs can be eliminated by increased water intake.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14204","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615349","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}
Luke S. Dunaway, Anthony K. Cook, Cailin E. Kellum, Claudia Edell, Davide Botta, Patrick A. Molina, Randee S. Sedaka, Livius V. d'Uscio, Zvonimir S. Katusic, David M. Pollock, Edward W. Inscho, Jennifer S. Pollock
Aim
We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism.
Methods
Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured.
Results
We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling.
Conclusion
We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.
目的：我们旨在验证高盐饮食（HS）通过组蛋白去乙酰化酶1（HDAC1）依赖机制损害肾脏微血管内皮细胞NO信号转导的假设：雄性 Sprague Dawley 大鼠喂食正常盐饮食（NS；0.49% NaCl）或 HS（4% NaCl）2 周。使用血液灌流的并髓质肾小球（JMN）制备方法，通过测量 L-NAME 诱导的传入动脉血管收缩来评估 NO 信号传导。在这种制备方法中，肾脏灌注的血液来自与肾脏供体饮食相同或不同的供体大鼠。用磁性激活细胞分选法分离肾脏内皮细胞，并测定 HDAC1 的活性：结果：我们发现 HS 会导致传入动脉中的 NO 信号转导受损。用 MS-275 抑制 HDAC1 后，这一现象得以恢复。与这些发现一致的是，肾脏内皮细胞中 HDAC1 的活性增加。我们进一步发现，NO 的损失取决于供血者的饮食，而不是供肾者的饮食。这表明存在一种体液因素，我们称之为血浆源性内皮功能障碍介质（PDEM）。使用抗氧化剂 PEG-SOD 和 PEG 催化酶以及 NOS 辅因子四氢生物蝶呤进行预处理后，NO 信号转导得以恢复：我们得出结论：HS 通过 PDEM 激活内皮 HDAC1，导致 NO 信号转导减少。本研究为了解 HS 降低肾微血管内皮 NO 信号传导的分子机制提供了新的视角。
{"title":"Endothelial histone deacetylase 1 activity impairs kidney microvascular NO signaling in rats fed a high-salt diet","authors":"Luke S. Dunaway, Anthony K. Cook, Cailin E. Kellum, Claudia Edell, Davide Botta, Patrick A. Molina, Randee S. Sedaka, Livius V. d'Uscio, Zvonimir S. Katusic, David M. Pollock, Edward W. Inscho, Jennifer S. Pollock","doi":"10.1111/apha.14201","DOIUrl":"10.1111/apha.14201","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615348","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>Physiologically occurring programming processes, inherent within biological systems, govern the development and function of organisms. Driven by genetic and epigenetic factors, these processes dictate cellular differentiation, organ development, and physiological responses. Understanding the intricacies of natural biological programming offers insights into how cells and tissues self-organize, adapt, and repair, with a perspective toward advances in regenerative medicine, disease prevention, and therapeutic innovation. A better understanding of these intrinsic programming mechanisms may, in the future, enable novel biomedical applications.</p><p><i>Foetal metabolic programming</i> and <i>metabolic maturation</i> are interconnected processes that shape an individual's metabolic health from early development through adulthood.<span><sup>1</sup></span></p><p><i>Foetal metabolic programming</i>, a critical concept in developmental biology, examines how environmental factors during pregnancy influence the long-term health and disease susceptibility of the offspring.<span><sup>2</sup></span> This field investigates the mechanisms by which prenatal exposures, such as nutrition, stress, and toxins, can alter foetal development,<span><sup>3</sup></span> potentially leading to chronic conditions such as obesity, diabetes, and cardiovascular disease later in life.<span><sup>4</sup></span> Gestational diabetes mellitus is an acquired glucose intolerance with onset or first detection during pregnancy. It affects up to a fifth of all pregnant women and usually disappears after delivery.<span><sup>5</sup></span> Foetal exposure to maternal gestational diabetes increases the risk of a multitude of adverse health outcomes for both mother and child, and is probably modified by maternal body weight. Therefore, improving glucose and weight control during pregnancy or before conception could reduce the risk to the offspring.<span><sup>6</sup></span> Weight control during pregnancy is mostly relevant for women who either are obese when they get pregnant, or who gain weight too quickly during pregnancy. While a pregnant woman should not go on a diet or try to lose weight during pregnancy, a focus on healthy nutrition and physical activity is helpful. Data indicate that obese women before pregnancy may benefit from recommendations regarding, for example, time-restricted eating<span><sup>7, 8</sup></span> and avoiding specific obesogenic habits such as late-night snacking<span><sup>9</sup></span> or sedentary lifestyle choices.<span><sup>10</sup></span> As current data also indicate a differential benefit of exercise for weight control at specific times during the day<span><sup>11</sup></span> and an influence of exercise-induced organ crosstalk on energy metabolism,<span><sup>12</sup></span> more data are needed to give specific recommendations for tailoring lifestyle interventions to the needs of this specific demographic. Understanding foetal programming and its im
{"title":"Physiological programming, adaptation, and regeneration","authors":"Pontus B. Persson, Anja Bondke Persson","doi":"10.1111/apha.14207","DOIUrl":"10.1111/apha.14207","url":null,"abstract":"<p>Physiologically occurring programming processes, inherent within biological systems, govern the development and function of organisms. Driven by genetic and epigenetic factors, these processes dictate cellular differentiation, organ development, and physiological responses. Understanding the intricacies of natural biological programming offers insights into how cells and tissues self-organize, adapt, and repair, with a perspective toward advances in regenerative medicine, disease prevention, and therapeutic innovation. A better understanding of these intrinsic programming mechanisms may, in the future, enable novel biomedical applications.</p><p><i>Foetal metabolic programming</i> and <i>metabolic maturation</i> are interconnected processes that shape an individual's metabolic health from early development through adulthood.<span><sup>1</sup></span></p><p><i>Foetal metabolic programming</i>, a critical concept in developmental biology, examines how environmental factors during pregnancy influence the long-term health and disease susceptibility of the offspring.<span><sup>2</sup></span> This field investigates the mechanisms by which prenatal exposures, such as nutrition, stress, and toxins, can alter foetal development,<span><sup>3</sup></span> potentially leading to chronic conditions such as obesity, diabetes, and cardiovascular disease later in life.<span><sup>4</sup></span> Gestational diabetes mellitus is an acquired glucose intolerance with onset or first detection during pregnancy. It affects up to a fifth of all pregnant women and usually disappears after delivery.<span><sup>5</sup></span> Foetal exposure to maternal gestational diabetes increases the risk of a multitude of adverse health outcomes for both mother and child, and is probably modified by maternal body weight. Therefore, improving glucose and weight control during pregnancy or before conception could reduce the risk to the offspring.<span><sup>6</sup></span> Weight control during pregnancy is mostly relevant for women who either are obese when they get pregnant, or who gain weight too quickly during pregnancy. While a pregnant woman should not go on a diet or try to lose weight during pregnancy, a focus on healthy nutrition and physical activity is helpful. Data indicate that obese women before pregnancy may benefit from recommendations regarding, for example, time-restricted eating<span><sup>7, 8</sup></span> and avoiding specific obesogenic habits such as late-night snacking<span><sup>9</sup></span> or sedentary lifestyle choices.<span><sup>10</sup></span> As current data also indicate a differential benefit of exercise for weight control at specific times during the day<span><sup>11</sup></span> and an influence of exercise-induced organ crosstalk on energy metabolism,<span><sup>12</sup></span> more data are needed to give specific recommendations for tailoring lifestyle interventions to the needs of this specific demographic. Understanding foetal programming and its im","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615350","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}
Celia Piquer-Martinez, Maria Isabel Valverde-Merino, Manuel Gomez-Guzman, Maria Jose Zarzuelo
<p>Education in health careers is changing drastically aligning itself with a more patient-oriented approach.<span><sup>1</sup></span> The use of valid and reliable instruments to assess these new skills, such as communication or ability to think critically, essentially ensures the quality of emerging professionals. Gamification has emerged as an innovative approach to enhance learning experiences by integrating game mechanics into educational settings. By incorporating rules, competition, conflict, challenge and storytelling, gamification creates an engaging and immersive environment for learners.<span><sup>2</sup></span> </p><p>Within this evolving landscape, students have embraced the use of mobile applications (apps) as valuable tools for accessing educational materials, study aids, and patient-care resources. These apps empower students to engage in flexible and personalized learning experiences, allowing them to learn at their own pace and convenience.</p><p>It has been repeatedly demonstrated that the spatial abilities associated with success in the educational and professional fields of Science, Technology, Engineering, and Mathematics (STEM) are gendered, with males demonstrating clearly superior spatial abilities to females.<span><sup>3</sup></span> </p><p>Despite the potential benefits, there is still a lack of research examining the impact of apps on education in health careers. Studies in university students, have observed gender differences, such as in the mediating role of the exercise environment in the relationship between exercise engagement and exercise adherence, not existing in male university students, while it does in female university students.<span><sup>4</sup></span> </p><p>Within the context of education in health careers, the impact of mobile apps in classrooms on student satisfaction and academic performance has been a subject of several investigations. Students who utilized mobile health applications not only rated themselves favorably but also felt better prepared to collaborate with individuals from other disciplines compared to their peers who did not use such apps. Alhaddad in 2018 reported that students who engaged with a mobile app for drug calculation practice experienced significant enhancements in their performance relative to counterparts relying on conventional paper-based methods.<span><sup>5</sup></span> Most recently, in 2022, Fathelrahman et al. demonstrated that students who accessed course materials and quizzes via a mobile app expressed greater satisfaction with their learning experience than those who did not utilize such technological tools.<span><sup>6</sup></span> </p><p>Male students showed greater improvement in learning outcomes compared to female students. This is somewhat surprising given previous research on gender differences in learning styles and preferences. The inclusion of gamification features seems to have the potential to increase us
{"title":"Gender-based differences in gamification and mobile learning","authors":"Celia Piquer-Martinez, Maria Isabel Valverde-Merino, Manuel Gomez-Guzman, Maria Jose Zarzuelo","doi":"10.1111/apha.14206","DOIUrl":"10.1111/apha.14206","url":null,"abstract":"<p>Education in health careers is changing drastically aligning itself with a more patient-oriented approach.<span><sup>1</sup></span> The use of valid and reliable instruments to assess these new skills, such as communication or ability to think critically, essentially ensures the quality of emerging professionals. Gamification has emerged as an innovative approach to enhance learning experiences by integrating game mechanics into educational settings. By incorporating rules, competition, conflict, challenge and storytelling, gamification creates an engaging and immersive environment for learners.<span><sup>2</sup></span>\u0000 </p><p>Within this evolving landscape, students have embraced the use of mobile applications (apps) as valuable tools for accessing educational materials, study aids, and patient-care resources. These apps empower students to engage in flexible and personalized learning experiences, allowing them to learn at their own pace and convenience.</p><p>It has been repeatedly demonstrated that the spatial abilities associated with success in the educational and professional fields of Science, Technology, Engineering, and Mathematics (STEM) are gendered, with males demonstrating clearly superior spatial abilities to females.<span><sup>3</sup></span>\u0000 </p><p>Despite the potential benefits, there is still a lack of research examining the impact of apps on education in health careers. Studies in university students, have observed gender differences, such as in the mediating role of the exercise environment in the relationship between exercise engagement and exercise adherence, not existing in male university students, while it does in female university students.<span><sup>4</sup></span>\u0000 </p><p>Within the context of education in health careers, the impact of mobile apps in classrooms on student satisfaction and academic performance has been a subject of several investigations. Students who utilized mobile health applications not only rated themselves favorably but also felt better prepared to collaborate with individuals from other disciplines compared to their peers who did not use such apps. Alhaddad in 2018 reported that students who engaged with a mobile app for drug calculation practice experienced significant enhancements in their performance relative to counterparts relying on conventional paper-based methods.<span><sup>5</sup></span> Most recently, in 2022, Fathelrahman et al. demonstrated that students who accessed course materials and quizzes via a mobile app expressed greater satisfaction with their learning experience than those who did not utilize such technological tools.<span><sup>6</sup></span>\u0000 </p><p>Male students showed greater improvement in learning outcomes compared to female students. This is somewhat surprising given previous research on gender differences in learning styles and preferences. The inclusion of gamification features seems to have the potential to increase us","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14206","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578331","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}
Tanawat Attachaipanich, Siriporn C. Chattipakorn, Nipon Chattipakorn
Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.
{"title":"Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations","authors":"Tanawat Attachaipanich, Siriporn C. Chattipakorn, Nipon Chattipakorn","doi":"10.1111/apha.14199","DOIUrl":"10.1111/apha.14199","url":null,"abstract":"<p>Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562031","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}
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