American journal of physiology. Regulatory, integrative and comparative physiology最新文献

{"title":"Aged aortic perivascular adipose tissue exacerbates aortic stiffness in mice.","authors":"David J Buckley, Kidist Bogale, Nathan Cuellar, Alexandra Canizales, Konner J Terrebonne, Katherine A Smith, Jacopo Ferruzzi, Rhonda D Prisby, Daniel W Trott","doi":"10.1152/ajpregu.00223.2026","DOIUrl":"10.1152/ajpregu.00223.2026","url":null,"abstract":"<p><p>Aging is characterized by progressive large artery stiffening, a major risk factor for cardiovascular disease. The aorta is surrounded by aortic perivascular adipose tissue (APVAT), which has been shown to contribute to greater compliance in young healthy rodents in ex vivo assessments of aortic stiffness. However, whether APVAT maintains this positive influence on compliance with advancing age is unknown. Therefore, we assessed ex vivo aortic stiffness with APVAT either intact or removed in young (4-6 mo) and old (22-25 mo) mice. In young mice, aortic stiffness did not differ between vessels with intact APVAT and those with APVAT removed. In contrast, in old mice, aortic stiffness was significantly greater when APVAT was left intact compared with cleaned aortas, indicating that aged APVAT exerts a detrimental influence on aortic stiffness. To explore potential mechanisms, we assessed collagen deposition within APVAT and found that aged mice exhibited significantly greater APVAT-specific collagen accumulation compared with young animals. These findings suggest that with aging, APVAT undergoes fibrotic remodeling that contributes to increased aortic stiffness.<b>NEW & NOTEWORTHY</b> We show that the mechanical influence of APVAT on the aorta is strongly age-dependent. In contrast to young animals, aged APVAT increases passive aortic stiffness and displays increased collagen deposition, implicating fibrotic remodeling of APVAT as a novel contributor to age-related arterial stiffening.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R666-R670"},"PeriodicalIF":2.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional and molecular skeletal muscle responses to aerobic exercise in rat models of acute and chronic doxorubicin exposure.","authors":"Carolina R Tonon, Bertha F Polegato, Daniela S Inoue, Quinten W Pigg, Dillon R Harris, Riya Meka, Advait Dadi, Mariana Janini Gomes","doi":"10.1152/ajpregu.00108.2026","DOIUrl":"10.1152/ajpregu.00108.2026","url":null,"abstract":"<p><p>This study examined the effects of aerobic exercise on skeletal muscle function, structure, and molecular markers following acute and chronic doxorubicin (DOX) exposure. Fifty-six male Wistar rats were assigned to acute (20 mg/kg, single dose) or chronic DOX (5 mg/kg/wk, 3 doses) protocols. In both protocols, rats were allocated in four groups: control (C, <i>n</i> = 6), control exercise (control Ex, <i>n</i> = 6), DOX (DOX, <i>n</i> = 8), and DOX exercise (DOX Ex, <i>n</i> = 8). A 4-wk aerobic exercise was performed on a treadmill before acute DOX (preconditioning) or during chronic DOX treatment (concomitant). Muscle function was assessed by electrical stimulation, and tibialis anterior muscle was analyzed. Data were analyzed using two-way ANOVA (<i>P</i> < 0.05). Acute DOX significantly reduced body and muscle mass, increased low-frequency muscle torque, and impaired muscle relaxation, accompanied by calpain-mediated proteolysis and increased p67phox and catalase expression. Exercise preconditioning significantly reduced circulating basal creatine kinase and modulated sarcoplasmic reticulum Ca²⁺ ATPase (SERCA)1 expression in skeletal muscle. Chronic DOX significantly reduced body mass, muscle mass, size, and function, with a significant increase in plasma malondialdehyde. Inflammatory cytokines were significantly elevated only acutely. Concomitant exercise significantly attenuated calpain-mediated proteolysis in DOX-treated rats and increased glutathione peroxidase expression in control animals. In conclusion, DOX-induced skeletal muscle dysfunction with acute alterations in proteins involved in calcium regulation. In the chronic model, DOX-induced muscle atrophy, muscle dysfunction, and systemic oxidative stress. Although aerobic exercise attenuated calpain-mediated proteolysis in both acute and chronic models, only exercise preconditioning increased SERCA1 expression, highlighting the importance of exercise timing for mitigating DOX-induced muscle alterations.<b>NEW & NOTEWORTHY</b> The success of DOX chemotherapy in improving cancer survival has led to a growing population of survivors; however, this has also highlighted long-term treatment-related effects affecting skeletal muscle. We demonstrate that acute DOX exposure is characterized by systemic inflammation and altered muscle contractility, whereas chronic administration is characterized by oxidative stress and reduced muscle function. Aerobic exercise confers greater muscle protection when applied as a preconditioning strategy.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R647-R660"},"PeriodicalIF":2.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consideration of resting retrograde shear on endothelial function as assessed by flow-mediated dilation in healthy adults.","authors":"Taha A Alhalimi, Ziba Taherzadeh, Zachary R Oldham, Claire E Kissell, Prema Velusamy, Damsara Nandadeva, Ann-Katrin Grotle, Jaume Padilla, Paul J Fadel","doi":"10.1152/ajpregu.00250.2026","DOIUrl":"10.1152/ajpregu.00250.2026","url":null,"abstract":"<p><p>Shear patterns influence endothelial function. Indeed, previous cell and animal studies have demonstrated that experimentally induced elevations in retrograde shear impair endothelial function. Similarly, experimental augmentation of retrograde shear in humans has been shown to reduce endothelial function in healthy adults. To date, no studies have investigated whether resting retrograde shear influences measures of endothelial function. Thus, we hypothesized that having higher retrograde shear rate (SR) and oscillatory shear index (OSI) at rest is associated with lower flow-mediated dilation (FMD) measures in healthy adults. Brachial artery FMD, retrograde SR, and OSI were measured using duplex Doppler ultrasound in 88 healthy adults (18-45 yr; 46 females). FMD was negatively correlated with resting retrograde SR (<i>r</i> = -0.307, <i>P</i> = 0.004), and this relationship was similar in males (<i>r</i> = -0.310, <i>P</i> = 0.045) and females (<i>r</i> = -0.326, <i>P</i> = 0.027). Likewise, FMD was negatively correlated with OSI in the full cohort (<i>r</i> = -0.403, <i>P</i> < 0.001) and in males and females separately (males: <i>r</i> = -0.352, <i>P</i> = 0.022; females: <i>r</i> = -0.446, <i>P</i> = 0.002). Furthermore, subgroup analyses based on magnitude of retrograde SR (in tertiles) demonstrated that participants with the highest retrograde SR and OSI at rest had the lowest FMD values (e.g., no retrograde SR, FMD: 8.6 ± 4.2%; <i>tertile 1</i> retrograde SR: 3.9 ± 2.1 -s^-1, FMD: 6.9 ± 2.8%; <i>tertile 2</i> retrograde SR: 13.5 ± 4.0 -s^-1, FMD: 5.7 ± 3.1%; and <i>tertile 3</i> retrograde SR: 42.8 ± 21.1 -s^-1, FMD: 4.6 ± 2.1%, <i>P</i> < 0.001). Collectively, these findings suggest that having higher baseline resting retrograde SR and OSI before FMD measures is associated with lower FMD values in healthy adults.<b>NEW & NOTEWORTHY</b> Herein, we show that having elevated resting retrograde shear directly before measuring flow-mediated dilation (FMD) is associated with a lower FMD response in healthy adults. Likewise, subgroup analyses revealed that participants with the highest resting retrograde shear had the lowest FMD values. These results emphasize the importance of considering resting retrograde shear patterns in studies measuring FMD, especially for group comparisons or pre- and postinterventional studies in healthy adults.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R661-R665"},"PeriodicalIF":2.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermal environment and light exposure shape sleep-associated metabolic and thermoregulatory rhythms.","authors":"Kara R Gouwens, Yibing Nong, Bradford G Hill, Matthew A Nystoriak","doi":"10.1152/ajpregu.00061.2026","DOIUrl":"10.1152/ajpregu.00061.2026","url":null,"abstract":"<p><p>Sleep, metabolism, and thermoregulation are coordinated physiological processes that are modulated by the external environment. This study investigated how sleep-wake state is associated with metabolic substrate utilization and thermoregulatory rhythms, and how these relationships are modified by thermal and light-dark conditions. Using continuous electroencephalography, electromyography, indirect calorimetry, and body temperature monitoring in freely moving mice, we examined the baseline metabolic and thermoregulatory fluctuations across sleep-wake states, the impact of ambient temperature, and the influence of light exposure. Our results demonstrate that sleep onset is associated with reduced energy expenditure, increased relative fat oxidation (lower respiratory exchange ratio, RER), and decreased body temperature in a cold (21°C) environment. These effects were attenuated under thermoneutral conditions (30°C). Short-term restricted-light/extended-dark exposure (18 h dark:6 h light) had limited effects on total sleep duration and thermoregulatory rhythms under the conditions tested, but altered sleep-wake state-linked RER at thermoneutrality. These findings indicate that environmental temperature and short-term changes in light exposure conditions interact to modulate sleep-associated metabolic and thermoregulatory rhythms in mice. Our results thus support a model in which environmental context shapes energy-homeostatic adaptations during sleep and underscore the need for studies that directly test causal mechanisms.<b>NEW & NOTEWORTHY</b> Sleep onset in freely moving mice is associated with a shift toward lower RER and reduced body temperature. Thermoneutral temperatures blunt sleep-linked metabolic and thermal signatures while increasing total sleep duration. Short-term restricted light exposure (18 h dark:6 h light) produced limited effects on sleep duration and thermoregulatory rhythms under the conditions tested, yet altered RER at thermoneutrality, suggesting that light exposure and ambient temperature can jointly tune sleep-associated energy metabolism.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R623-R632"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-load blood flow restriction training and ischemia modulate expression of Na⁺,K⁺-ATPase and FXYDs in human skeletal muscle.","authors":"Vid Jan, Katarina Miš, Alan Kacin, Anja Vidović, Tina Tomc Žargi, Klemen Stražar, Matej Podbregar, Tomaž Marš, Matej Drobnič, Alexander V Chibalin, Sergej Pirkmajer","doi":"10.1152/ajpregu.00340.2025","DOIUrl":"10.1152/ajpregu.00340.2025","url":null,"abstract":"<p><p>Anterior cruciate ligament (ACL) rupture leads to muscle deconditioning and downregulation of Na⁺,K⁺-ATPase (NKA). Low-load blood flow restriction (LL-BFR) training was shown to improve muscle function after ACL injury, but its effects on NKA are unknown. We analyzed the expression of NKA and its FXYD regulators in knee muscles from ACL-injured subjects undergoing LL-BFR, low-load training with sham blood flow restriction (LL-Sham), or no training (Control). In addition, we dissected effects of ischemia components by subjecting cultured human myotubes to glucose deprivation and/or hypoxia. The LL-BFR group had higher vastus lateralis mRNA levels of NKAα1 than the Control and LL-Sham groups. In vitro, NKAα1, NKAβ1, and NKAβ3 mRNA and NKAα1 and NKAβ1 protein levels were downregulated by sustained ischemia and glucose deprivation, but not hypoxia, whereas FXYD5 protein was upregulated by glucose deprivation. Conversely, intermittent ischemia had no effect on NKA or FXYD expression. In conclusion, LL-BFR training was associated with upregulation of NKAα1 mRNA levels in the vastus lateralis after ACL injury; however, in the absence of corresponding changes in protein abundance, its contribution to functional recovery remains unclear. Moreover, our in vitro findings suggest that glucose availability plays a major role in modulating NKA and FXYD expression in muscle cells under ischemic conditions.<b>NEW & NOTEWORTHY</b> This is the first study exploring effects of low-load BFR training on Na⁺,K⁺-ATPase (NKA) and FXYD expression in knee muscles after anterior cruciate ligament injury. Effects of ischemia components were analyzed by subjecting cultured human myotubes to glucose deprivation and/or hypoxia. The LL-BFR group had higher vastus lateralis mRNA levels of NKAα1 than the Control and LL-Sham groups. Glucose plays a major role in modulating NKA and FXYD expression in cultured myotubes under ischemic conditions.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R542-R558"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-intensity neuromuscular electrical stimulation elicits detectable metaboreflex-mediated sympathetic responses in humans.","authors":"Ryosuke Takeda, Shun Kunugi, Kohei Watanabe","doi":"10.1152/ajpregu.00185.2026","DOIUrl":"10.1152/ajpregu.00185.2026","url":null,"abstract":"<p><p>Neuromuscular electrical stimulation (NMES) augments sympathetic and pressor responses compared with voluntary contraction (VOL), even at low contraction intensities; however, the mechanisms underlying these responses remain incompletely understood. Under low-intensity, short-duration VOL, metaboreflex activation is typically minimal because metabolic stress is limited. Therefore, examining NMES under these conditions may provide insight into whether the unique activation pattern associated with electrically evoked contractions alters the conditions required for detectable metaboreflex-mediated sympathetic responses. Accordingly, we examined muscle sympathetic nerve activity (MSNA) and cardiovascular responses during low-intensity NMES with postexercise circulatory occlusion (PECO). Ten young adults completed two randomized tasks: VOL and NMES. Participants performed 30 s of isometric elbow flexion at ∼10% maximal voluntary torque, followed immediately by 2 min of PECO to isolate metaboreflex-mediated responses. MSNA was recorded using microneurography, and beat-by-beat blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were continuously measured. Compared with VOL, NMES elicited greater increases in systolic and diastolic arterial pressures during both contraction and PECO (main effect of condition, both <i>P</i> < 0.01). MSNA burst frequency and incidence also increased during NMES and remained elevated during PECO, whereas the corresponding responses during VOL were minimal (interaction, both <i>P</i> < 0.001). In contrast, HR, SV, CO, and TPR responses did not differ between conditions. These findings demonstrate that low-intensity, short-duration NMES can elicit detectable metaboreflex-mediated sympathetic and pressor responses under conditions in which such responses are typically minimal during voluntary exercise.<b>NEW & NOTEWORTHY</b> Low-intensity, short-duration neuromuscular electrical stimulation (NMES) elicited greater sympathetic and pressor responses than torque-matched voluntary contraction, and these responses persisted during postexercise circulatory occlusion. These findings provide novel evidence that detectable metaboreflex-mediated responses can occur during NMES even under low-intensity, short-duration conditions, suggesting that sympathetic neural and cardiovascular responses may differ despite comparable external force production.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R633-R645"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased energy expenditure through intermittent cold exposure does not enhance tirzepatide-induced weight loss in obese mice.","authors":"Annalaura Bellucci, Hadil Alfares, Clara Gale, Michael Akcan, Ben Waters, Katelyn Eisner, Bradley J Baranowski, Stewart Jeromson, Ailish Babicki-Moore, David C Wright","doi":"10.1152/ajpregu.00220.2026","DOIUrl":"10.1152/ajpregu.00220.2026","url":null,"abstract":"<p><p>Obesity results from an imbalance between energy intake and energy expenditure. Although pharmacological approaches such as tirzepatide, a dual gastric inhibitory protein/glucagon-like protein-1 receptor agonist, reduce food intake and body weight, enhancing energy expenditure via intermittent cold exposure (ICE)-induced activation of thermogenesis may provide complementary benefits. Intermittent cold exposure increases energy expenditure and improves glucose homeostasis independent of weight loss. The objective of this study was to investigate the individual and combined effects of tirzepatide and intermittent cold exposure (ICE) on weight loss and glucose homeostasis. We hypothesized that combining ICE with tirzepatide would lead to greater weight loss and improvements in glucose homeostasis than tirzepatide alone. Male and female C57BL/6J mice were fed a high-fat diet for 8 wk and then treated with tirzepatide (10 nmol/kg) or vehicle and exposed, or not, to ICE (4°C, 1 h/day, 5 days/wk) for 3 wk. Body weight/composition, energy expenditure, food intake, and glucose homeostasis were assessed. Tirzepatide reduced body weight, food intake, and adiposity in both sexes, whereas ICE acutely increased energy expenditure and improved glucose homeostasis independent of changes in body weight. There were no additive effects of combining tirzepatide and ICE. Our findings highlight that combining tirzepatide-mediated reduction in energy intake with ICE-induced activation of thermogenesis yields complementary, but not necessarily additive improvements in metabolic health.<b>NEW & NOTEWORTHY</b> The combined effects on metabolic health of reduced energy intake with tirzepatide and increased energy expenditure via intermittent cold exposure have not been examined. Despite increasing energy expenditure and improving glucose homeostasis, intermittent cold exposure did not augment tirzepatide-induced weight loss or improvements in glucose metabolism. These findings indicate that, in this model, pharmacological reduction of energy intake is more effective than transient, cold-induced increases in thermogenesis for weight loss and adiposity.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R609-R622"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kcnj15, but not Kcnj1, localizes with Nkcc2 in the apical membranes of renal tubular and intestinal epithelial cells of marine pufferfish, <i>Takifugu rubripes</i>.","authors":"Yohei Sakamoto, Keiichiro Fujimori, Yutaka Suzuki, Akira Kato","doi":"10.1152/ajpregu.00287.2023","DOIUrl":"10.1152/ajpregu.00287.2023","url":null,"abstract":"<p><p>In mammals, Na⁺-K⁺-2Cl^- cotransporter 2 (Nkcc2) is localized in the apical membrane of the renal tubule and contributes to salt reabsorption. Nkcc2 localizes with K⁺ channels, such as the potassium inwardly rectifying channel subfamily J member 1 (Kcnj1), which provide K⁺ to the luminal fluid. In marine teleosts, Nkcc2 is expressed in the kidneys and intestine; however, the K⁺ channels localizing with it remain ambiguous. Here, tissue distribution analysis revealed that the paralogs of <i>kcnj1</i> were expressed in the gills and other organs but not in the kidneys and intestines of the marine pufferfish, <i>Takifugu rubripes</i>. In contrast, <i>kcnj15</i> was highly expressed in the kidneys, intestine, gills, and urinary bladder of the pufferfish. Immunohistochemical analysis showed that Kcnj15 localizes to the apical region with Nkcc2 and to the basolateral region with Na⁺/K⁺-ATPase (Nka) in the renal tubules and intestinal epithelial cells of marine pufferfish. The expression of <i>kcnj15</i>, <i>nkcc2</i>, and Na⁺-Cl^- cotransporter (<i>ncc</i>) in the kidney was significantly increased in brackish water (1 ppt salinity) compared with that in seawater (35 ppt). In brackish water, Kcnj15 was localized to the basolateral side with Nka in the renal tubules. In the urinary bladder, Kcnj15 was localized to the basolateral side along with Nka in Ncc-positive epithelial cells in both seawater and brackish water. These results suggest that Kcnj15 is involved in the salt (re)absorption systems of the urinary and digestive systems in pufferfish in a manner dependent on the expressing cells and habitat salinity.<b>NEW & NOTEWORTHY</b> Nkcc2 plays an important role in salt (re)absorption in the intestines and kidneys of seawater teleosts. However, the K⁺ channels that recycle K⁺ for the Nkcc2 function remain unknown. This study revealed that Kcnj15 is localized to the apical region of Nkcc2-positive nephron segments and intestinal epithelial cells and is also present at the basolateral region with Nka. Our results provide insights into the mechanisms underlying water-electrolyte metabolism in teleosts.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R583-R608"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CX3CL1-CX3CR1 axis in HIV-associated inflammation and cardiometabolic disease.","authors":"Ronald K McMillan, Annet Kirabo, John R Koethe, Celestine N Wanjalla","doi":"10.1152/ajpregu.00140.2026","DOIUrl":"10.1152/ajpregu.00140.2026","url":null,"abstract":"<p><p>The chemokine fractalkine (CX3CL1)-chemokine (CX3C motif) receptor 1 (CX3CR1) axis, comprising the chemokine fractalkine (CX3CL1) and its immune cell receptor CX3CR1, links immune activation to vascular pathology in people with human immunodeficiency virus (HIV; PWH). Chronic inflammation persists in PWH despite viral suppression with antiretroviral therapy and contributes to high rates of cardiometabolic comorbidities. This is partly due to dysregulated leukocyte trafficking and endothelial activation. This review synthesizes preclinical, genetic, and clinical evidence on the multifaceted roles of CX3CR1 across immune, vascular, and cardiometabolic processes. CX3CR1 is expressed on monocyte and cytotoxic T cell subsets implicated in endothelial injury, tissue trafficking, and plaque progression. On the other hand, CX3CL1 is expressed on activated endothelial and stromal cells, which promotes leukocyte adhesion and recruitment into inflamed tissues. In PWH, persistent immune activation and cytomegalovirus coinfections are associated with the expansion of differentiated CX3CR1-expressing T cell populations, supporting the relevance of this pathway to HIV-associated inflammatory comorbidities. At the genetic level, CX3CR1 polymorphisms, including V249I and T280M, alter receptor signaling and have been associated with HIV disease progression and cardiovascular disease risk, highlighting CX3CR1 as both a biomarker and potential mediator of immune-driven pathology. Across preclinical models, pharmacological targeting of CX3CR1 or CX3CL1 attenuates inflammation, fibrosis, and vascular injury in the selected disease contexts. However, the effects of CX3CR1 signaling are tissue- and cell type-specific, and blockade may carry potential risks in settings where CX3CR1 supports immune surveillance, mucosal repair, or macrophage homeostasis. This review evaluates the therapeutic promise and safety considerations of targeting the CX3CL1-CX3CR1 axis in HIV-associated cardiovascular and inflammatory comorbidities.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R559-R575"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe heat stress exposure as a hidden driver of future cardiovascular disease: a narrative review of animal and human studies.","authors":"Ashley J Smuder, Joshua T Selsby, Melissa Roths, Ryan W Krueger, Thomas L Clanton","doi":"10.1152/ajpregu.00191.2026","DOIUrl":"10.1152/ajpregu.00191.2026","url":null,"abstract":"<p><p>The cardiovascular system is particularly vulnerable to damage from severe environmental heat stress in both humans and animals, particularly during exertion. However, the mechanisms underlying this vulnerability are not well understood, and the potential long-term impacts in surviving patients with subclinical symptoms are not well recognized in medical practice. Human case series have described cardiovascular damage in some heat injury victims, but linking these to more general risks in adult healthy populations is difficult. However, in recent years, preclinical animal models in a variety of species have provided new insights into cause-and-effect outcomes, broadening our understanding of pathophysiological mechanisms, but many questions remain. This review looks at what is known about short- and long-term cardiovascular consequences of two contrasting types of heat exposures in animals. The first is passive heat lasting 24 h or more, mimicking conditions of environmental heat waves. The second is acute, exertional heat injury, designed to mimic conditions of intense exercise in the heat as experienced by athletes, military personnel, or outdoor laborers. Evidence is provided that both can induce substantial acute damage to the myocardium that could contribute to long-term cardiovascular complications. The potential mechanisms for long-term effects on the heart include direct impacts on Ca²⁺ regulation, metabolic control, and inflammation; indirect effects from gut, kidney, or endothelial damage; and dyssynchronous adrenergic myocardial activation, i.e., typical of stress-induced heart disease (takotsubo syndrome). The study highlights the need for future clinical and basic research in the long-term cardiovascular risks of all forms of severe environmental heat exposures.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R524-R541"},"PeriodicalIF":2.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}