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  • American Physiological Society  (22)
  • 2020-2024  (22)
  • Biology  (22)
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  • American Physiological Society  (22)
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  • 2020-2024  (22)
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  • 1
    Online Resource
    Online Resource
    Importance of β 2 AR elevation for re-endothelialization capacity mediated by late endothelial progenitor cells in hypertensive patients
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 320, No. 2 ( 2021-02-01), p. H867-H880
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 320, No. 2 ( 2021-02-01), p. H867-H880
    Abstract: Dysfunction of late endothelial progenitor cells (EPCs) has been suggested to be associated with hypertension. β 2 -Adrenergic receptor (β 2 AR) is a novel and key target for EPC homing. Here, we proposed that attenuated β 2 AR signaling contributes to EPCs dysfunction, whereas enhanced β 2 AR signaling restores EPCs’ functions in hypertension. EPCs derived from hypertensive patients exhibited reduced cell number, impaired in vitro migratory and adhesion abilities, and impaired re-endothelialization after transplantation in nude mice with carotid artery injury. β 2 AR expression of EPCs from hypertensive patients was markedly downregulated, whereas the phosphorylation of the p38 mitogen-activated protein kinase (p38-MAPK) was elevated. The cleaved caspase-3 levels were elevated in EPCs. The overexpression of β 2 AR in EPCs from hypertensive patients inhibited p38-MAPK signaling, whereas it enhanced in vitro EPC proliferation, migration, and adhesion and in vivo re-endothelialization. The β 2 AR-mediated effects were attenuated by treating the EPCs with a neutralizing monoclonal antibody against β 2 AR, which could be partially antagonized by the p38-MAPK inhibitor SB203580. Moreover, shear stress stimulation, a classic nonpharmacological intervention, increased the phosphorylation levels of β 2 AR and enhanced the in vitro and in vivo functions of EPCs from hypertensive patients. Collectively, the current investigation demonstrated that impaired β 2 AR/p38-MAPK/caspase-3 signaling at least partially reduced the re-endothelialization capacity of EPCs from hypertensive patients. Restoration of β 2 AR expression and shear stress treatment could improve their endothelial repair capacity by regulating the p38-MAPK/caspase-3 signaling pathway. The clinical significance of β 2 AR in endothelium repair still requires further investigation. NEW & NOTEWORTHY Impaired β 2 -adrenergic receptor (β 2 AR) expression with an elevation of p38-MAPK/caspase-3 signaling at least partially contributes to the decline of re-endothelialization capacity of late endothelial progenitor cells (EPCs) from hypertensive patients. β 2 AR gene transfer and shear stress treatment improve the late EPC-mediated enhancement of the re-endothelialization capacity in hypertensive patients through activating β 2 AR/p38-MAPK/caspase-3 signaling. The present study is the first to reveal the potential molecular mechanism of the impaired endothelium-reparative capacity of late EPCs in hypertension after vascular injury and strongly suggests that β 2 AR is a novel and crucial therapeutic target for increasing EPC-mediated re-endothelialization capacity in hypertension.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00596.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Coronary heart disease and atrial fibrillation: a vicious cycle
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 320, No. 1 ( 2021-01-01), p. H1-H12
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 320, No. 1 ( 2021-01-01), p. H1-H12
    Abstract: The population suffering from coronary heart disease (CHD) complicated by atrial fibrillation (AF) is rising rapidly. A strong correlation between the two diseases has been reported, and the many common risk factors they share may play prominent roles in their development. In addition, CHD can directly promote the progression of AF by affecting reentry formation, focal ectopic activity, and neural remodeling. At the same time, AF also affects CHD through three aspects: 1) atherosclerosis, 2) the mismatch of blood supply and oxygen consumption, and 3) thrombosis. In conclusion, CHD and AF can aggravate each other and seem to form a vicious cycle. For patients with CHD complicated by AF, principal studies and guidelines have focused on antithrombotic treatment and rhythm control, which are paramount for these patients. Of note, our review sheds light on the strategies to break the cycle of the two diseases, which may be fundamental to treat these patients and optimize the benefit.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00702.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Cell therapy attenuates endothelial dysfunction in hypertensive rats with heart failure and preserved ejection fraction
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 323, No. 5 ( 2022-11-01), p. H892-H903
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 323, No. 5 ( 2022-11-01), p. H892-H903
    Abstract: Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis. NEW & NOTEWORTHY We tested the concept that inflammation of endothelial cells is a major pathogenic factor in HFpEF. CDCs are heart-derived cell products with verified anti-inflammatory therapeutic properties. Infusion of CDCs reduced oxidative stress, restored eNOS abundance, lowered monocyte levels, and rescued the expression of multiple disease-associated genes, thereby restoring vascular reactivity. The salutary effects of CDCs support the hypothesis that inflammation of endothelial cells is a proximate driver of HFpEF. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/cell-therapy-and-endothelial-dysfunction-in-hfpef/ .
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00287.2022
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Atypical ALPK2 kinase is not essential for cardiac development and function
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 318, No. 6 ( 2020-06-01), p. H1509-H1515
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 318, No. 6 ( 2020-06-01), p. H1509-H1515
    Abstract: Protein kinases play an integral role in cardiac development, function, and disease. Recent experimental and clinical data have implied that protein kinases belonging to a family of atypical α-protein kinases, including α-protein kinase 2 (ALPK2), are important for regulating cardiac development and maintaining function via regulation of WNT signaling. A recent study in zebrafish reported that loss of ALPK2 leads to severe cardiac defects; however, the relevance of ALPK2 has not been studied in a mammalian animal model. To assess the role of ALPK2 in the mammalian heart, we generated two independent global Alpk2-knockout (Alpk2-gKO) mouse lines, using CRISPR/Cas9 technology. We performed physiological and biochemical analyses of Alpk2-gKO mice to determine the functional, morphological, and molecular consequences of Alpk2 deletion at the organismal level. We found that Alpk2-gKO mice exhibited normal cardiac function and morphology up to one year of age. Moreover, we did not observe altered WNT signaling in neonatal Alpk2-gKO mouse hearts. In conclusion, Alpk2 is dispensable for cardiac development and function in the murine model. Our results suggest that Alpk2 is a rapidly evolving gene that lost its essential cardiac functions in mammals. NEW & NOTEWORTHY Several studies indicated the importance of ALPK2 for cardiac function and development. A recent study in zebrafish report that loss of ALPK2 leads to severe cardiac defects. In contrast, murine Alpk2-gKO models developed in this work display no overt cardiac phenotype. Our results suggest ALPK2, as a rapidly evolving gene, lost its essential cardiac functions in mammals.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00249.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Autophagy, TERT, and mitochondrial dysfunction in hyperoxia
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 321, No. 5 ( 2021-11-01), p. H985-H1003
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 321, No. 5 ( 2021-11-01), p. H985-H1003
    Abstract: Ventilation with gases containing enhanced fractions of oxygen is the cornerstone of therapy for patients with hypoxia and acute respiratory distress syndrome. Yet, hyperoxia treatment increases free reactive oxygen species (ROS)-induced lung injury, which is reported to disrupt autophagy/mitophagy. Altered extranuclear activity of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), plays a protective role in ROS injury and autophagy in the systemic and coronary endothelium. We investigated interactions between autophagy/mitophagy and TERT that contribute to mitochondrial dysfunction and pulmonary injury in cultured rat lung microvascular endothelial cells (RLMVECs) exposed in vitro, and rat lungs exposed in vivo to hyperoxia for 48 h. Hyperoxia-induced mitochondrial damage in rat lungs [TOMM20, 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT)], which was paralleled by increased markers of inflammation [myeloperoxidase (MPO), IL-1β, TLR9] , impaired autophagy signaling (Beclin-1, LC3B-II/1, and p62), and decreased the expression of TERT. Mitochondrial-specific autophagy (mitophagy) was not altered, as hyperoxia increased expression of Pink1 but not Parkin. Hyperoxia-induced mitochondrial damage (TOMM20) was more pronounced in rats that lack the catalytic subunit of TERT and resulted in a reduction in cellular proliferation rather than cell death in RLMVECs. Activation of TERT or autophagy individually offset mitochondrial damage (MTT). Combined activation/inhibition failed to alleviate hyperoxic-induced mitochondrial damage in vitro, whereas activation of autophagy in vivo decreased mitochondrial damage (MTT) in both wild type (WT) and rats lacking TERT. Functionally, activation of either TERT or autophagy preserved transendothelial membrane resistance. Altogether, these observations show that activation of autophagy/mitophagy and/or TERT mitigate loss of mitochondrial function and barrier integrity in hyperoxia. NEW & NOTEWORTHY In cultured pulmonary artery endothelial cells and in lungs exposed in vivo to hyperoxia, autophagy is activated, but clearance of autophagosomes is impaired in a manner that suggests cross talk between TERT and autophagy. Stimulation of autophagy prevents hyperoxia-induced decreases in mitochondrial metabolism and sustains monolayer resistance. Hyperoxia increases mitochondrial outer membrane (TOMM20) protein, decreases mitochondrial function, and reduces cellular proliferation without increasing cell death.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00166.2021
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Belumosudil, ROCK2-specific inhibitor, alleviates cardiac fibrosis by inhibiting cardiac fibroblasts activation
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 323, No. 1 ( 2022-07-01), p. H235-H247
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 323, No. 1 ( 2022-07-01), p. H235-H247
    Abstract: Cardiac fibrosis is thought to be the hallmark of pathological hypertrophic remodeling, of which the myofibroblast transdifferentiation is the key cell biological event. However, there is still no specific and effective therapeutic agent approved for cardiac fibrosis. To investigate the effects of belumosudil, the first ρ-associated kinase-2 (ROCK2)-specific inhibitor, on cardiac hypertrophy, fibrosis, and dysfunction induced by pressure overload, the transverse aortic constriction (TAC) or sham operation was carried out on wild-type C57BL/6 mice (male, 6–8 wk old) under pentobarbital anesthesia. After that, mice were randomly divided into three groups: sham operation + vehicle, TAC + vehicle, TAC + 50 mg·kg −1 ·day −1 belumosudil. We found that belumosudil effectively ameliorated cardiac hypertrophy, fibrosis, and dysfunction in TAC mice. To elucidate the underlying mechanism, we inhibited the expression of ROCK2 in vitro by either belumosudil or siRNA. We showed that the inhibition of ROCK2 by either belumosudil or knockdown suppressed cardiac fibroblasts activation and proliferation significantly induced by transforming growth factor-β1 (TGF-β1). Furthermore, our study confirmed ROCK2 mediates cardiac fibrosis by interacting with TGF-β1/mothers against decapentaplegic homolog 2 (Smad2) pathway. Taken together, we demonstrated that belumosudil ameliorates cardiac hypertrophy and fibrosis induced by TAC via inhibiting cardiac fibroblasts activation. In conclusion, belumosudil may be a promising therapeutic drug for cardiac hypertrophy and fibrosis induced by myocardial pressure overload. NEW & NOTEWORTHY Although ρ-associated kinase-2 (ROCK2) is the main isoform of ρ-associated kinases (ROCKs) in the heart and more important in cardiac hypertrophy and fibrosis than ρ-associated kinase-1 (ROCK1), there has not been any pharmacological approach to inhibit ROCK2 selectively. Our study demonstrates for the first time that belumosudil, the first ROCK2-specific inhibitor, effectively ameliorates cardiac hypertrophy, fibrosis, and dysfunction induced by TAC via inhibiting cardiac fibroblasts activation.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00014.2022
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    Deep learning-based prediction of coronary artery stenosis resistance
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 323, No. 6 ( 2022-12-01), p. H1194-H1205
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 323, No. 6 ( 2022-12-01), p. H1194-H1205
    Abstract: Coronary artery stenosis resistance (SR) is a key factor for noninvasive calculations of fractional flow reserve derived from coronary CT angiography (FFR CT ). Existing computational fluid dynamics (CFD) methods, including three-dimensional (3-D) computational and zero-dimensional (0-D) analytical models, are usually limited by high calculation cost or low precision. In this study, we have developed a multi-input back-propagation neural network (BPNN) that can rapidly and accurately predict coronary SR. A training data set including 3,028 idealized anatomic coronary artery stenosis models was constructed for 3-D CFD calculation of SR with specific blood flow boundaries. Based on 3-D calculation results, we established a BPNN whose input is geometric parameters and blood flow, whereas output is SR. Then, a test set (324 cases) was constructed to evaluate the performance of the BPNN model. To verify the validity and practicability of the network, BPNN prediction results were compared with 3-D CFD and 0-D analytical model results from patient-specific models. For test set, the mean square error (MSE) between CFD and prediction results was 2.97%, linear regression analysis indicating a good correlation between the two ( P 〈 0.001). For 30 patient-specific models, the MSE of BPNN and the 0-D model were 3.26 and 9.7%, respectively. The calculation time for BPNN and the 3-D CFD model for 30 cases was about 2.15 s and 2 h, respectively. The present results demonstrate the practicability of using deep learning methods for fast and accurate predictions of coronary artery SR. Our study represents an advance in noninvasive calculations of FFR CT . NEW & NOTEWORTHY This study developed a multi-input back-propagation neural network (BPNN) that can be used to predict coronary artery stenosis resistance by inputting vascular geometric parameters and blood flow. Compared with previous studies, the network developed in this study can accurately and rapidly predict coronary artery stenosis resistance, which can not only meet clinical requirements but also reduce the cost of calculation duration. This study contributes to the noninvasive methods for the numerical calculation of fractional flow reserve derived from coronary CT angiography (FFRCT) and indicates that this technique can potentially be used for evaluating myocardial ischemia.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00269.2022
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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  • 8
    Online Resource
    Online Resource
    FGF21 promotes myocardial angiogenesis and mediates the cardioprotective effects of exercise in myocardial infarction mice
    American Physiological Society ; 2023
    In:  Journal of Applied Physiology Vol. 135, No. 3 ( 2023-09-01), p. 696-705
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 135, No. 3 ( 2023-09-01), p. 696-705
    Abstract: The mechanism by which aerobic exercise promotes cardiac function after myocardial infarction (MI) is still not fully understand. In this study, we investigated the role of fibroblast growth factor 21 (FGF21) in exercise protecting the cardiac function of MI mice. In vivo, MI was induced by left anterior descending coronary artery ligation in wild-type and fgf21 knockout mice on the C57BL/6 background. One week after MI, the mice underwent aerobic exercise for 4 wk. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with H 2 O 2 , recombinant human FGF21 (rhFGF21), fibroblast growth factor receptor 1 (FGFR1) inhibitor (PD166866), and phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) to explore the potential mechanisms. Scratch wound healing and tubule formation analysis were used to detect the migration and tubule formation ability of HUVECs. Our results showed that aerobic exercise significantly promoted angiogenesis and cardiac function through enhancing the expression of FGF21 and activating FGFR1/PI3K/AKT/VEGF pathway. But such changes in cardiac from aerobic exercise were attenuated by fgf21 knockout mice. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) enhanced angiogenesis and cell migration through FGF21/FGFR1/PI3K/AKT/VEGF signaling pathway. Under the intervention of H 2 O 2 , rhFGF21 also played the role of promoting angiogenesis and cell migration through the same mechanism. In conclusion, our results showed that FGF21 promoted the aerobic exercise-induced angiogenesis and improved cardiac function via FGFR1/PI3K/AKT/VEGF signal in MI mice. NEW & NOTEWORTHY FGF21 activated FGFR1/PI3K/AKT/VEGF signaling pathway mediated angiogenesis in MI mice. FGF21 deficiency attenuated aerobic exercise-induced cardiac angiogenesis in MI mice. FGF21/FGFR1/PI3K/AKT/VEGF signal played an important role in aerobic exercise to promote myocardial angiogenesis and improved cardiac function.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.00307.2023
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 9
    Online Resource
    Online Resource
    Demonstration of age-related blood-brain barrier disruption and cerebromicrovascular rarefaction in mice by longitudinal intravital two-photon microscopy and optical coherence tomography
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 320, No. 4 ( 2021-04-01), p. H1370-H1392
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 320, No. 4 ( 2021-04-01), p. H1370-H1392
    Abstract: Age-related blood-brain barrier (BBB) disruption and cerebromicrovascular rarefaction contribute importantly to the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Recent advances in geroscience research enable development of novel interventions to reverse age-related alterations of the cerebral microcirculation for prevention of VCID and AD. To facilitate this research, there is an urgent need for sensitive and easy-to-adapt imaging methods that enable longitudinal assessment of changes in BBB permeability and brain capillarization in aged mice and that could be used in vivo to evaluate treatment efficiency. To enable longitudinal assessment of changes in BBB permeability in aged mice equipped with a chronic cranial window, we adapted and optimized two different intravital two-photon imaging approaches. By assessing relative fluorescence changes over the baseline within a volume of brain tissue, after qualitative image subtraction of the brain microvasculature, we confirmed that, in 24-mo-old C57BL/6J mice, cumulative permeability of the microvessels to fluorescent tracers of different molecular masses (0.3 to 40 kDa) is significantly increased compared with that of 5-mo-old mice. Real-time recording of vessel cross-sections showed that apparent solute permeability of single microvessels is significantly increased in aged mice vs. young mice. Cortical capillary density, assessed both by intravital two-photon microscopy and optical coherence tomography was also decreased in aged mice vs. young mice. The presented methods have been optimized for longitudinal (over the period of 36 wk) in vivo assessment of cerebromicrovascular health in preclinical geroscience research. NEW & NOTEWORTHY Methods are presented for longitudinal detection of age-related increase in blood-brain barrier permeability and microvascular rarefaction in the mouse cerebral cortex by intravital two-photon microscopy and optical coherence tomography.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00709.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 10
    Online Resource
    Online Resource
    Periostin promotes arterial calcification through PPARγ-related glucose metabolism reprogramming
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 320, No. 6 ( 2021-06-01), p. H2222-H2239
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 320, No. 6 ( 2021-06-01), p. H2222-H2239
    Abstract: Extracellular matrix (ECM) exerts a series of biological functions and contributes to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the role of periostin in vascular calcification has yet to be fully investigated. As found in this study, recombinant periostin accelerated the thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS) ex vivo, which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition and suppressed PPARγ expression. Mechanistically, periostin caused overactivation of glycolysis and mitochondrial dysfunction in VSMCs as assessed by extracellular acidification rate, oxygen consumption rate, and mitochondrial respiratory chain complex activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients undergoing computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score in patients with coronary artery calcification (CAC). There was also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis. NEW & NOTEWORTHY Periostin caused arterial calcification, overactivated glycolysis, and damaged OXPHOS. PPARγ agonists alleviated periostin-promoted arterial calcification and corrected abnormal glycolysis and unbalanced mitochondrial homeostasis. There exists a relationship between periostin and lactate in patients with CAC.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01009.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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