Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Dirk Westermann ◽  
Olga Lettau ◽  
Meike Sobirey ◽  
Alexander Riad ◽  
Michael Bader ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Mrna Levels ◽  
Western Blots ◽  
Cardiac Inflammation ◽  
Akt Activation ◽  
B1 Receptor ◽  
Kinin B1 Receptor

Abstract Clinical use of the anthracycline doxorubicin (DOX) is limited by its cardiotoxic effects, which are attributed to the induction of apoptosis. To elucidate the possible role of the kinin B1 receptor (B1R) during the development of DOX cardiomyopathy, we studied B1R knockout mice (B1R-/-) by investigating cardiac inflammation and apoptosis after induction of DOX-induced cardiomyopathy. DOX control mice showed cardiac dysfunction measured by pressure-volume loops in vivo. This was associated with a reduced activation state of AKT, as well as an increased bax/bcl2 ratio in Western blots, indicating cardiac apoptosis. Furthermore, mRNA levels of the proinflammatory cytokine interleukin 6 were increased in the cardiac tissue. In DOX B1R-/- mice, cardiac dysfunction was improved compared to DOX control mice, which was associated with normalization of the bax/bcl-2 ratio and interleukin 6, as well as AKT activation state. These findings suggest that B1R is detrimental in DOX cardiomyopathy in that it mediates the inflammatory response and apoptosis. These insights might have useful implications for future studies utilizing B1R antagonists for treatment of human DOX cardiomyopathy.

scholarly journals Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin-Tong Wang ◽  
Zhen Peng ◽  
Ying-Ying An ◽  
Ting Shang ◽  
Guangxu Xiao ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Myocardial Dysfunction ◽  
Cecal Ligation ◽  
Hydroxysafflor Yellow A ◽  
Sepsis Management ◽  
Xuebijing Injection

Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

Abstract 88: Microrna-21* Controls Sepsis-induced Cardiac Dysfunction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hui Wang ◽  
Yihua Bei ◽  
Jing Shi ◽  
Wei Sun ◽  
Hui Liu ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Contractility ◽  
Cardiac Metabolism ◽  
Myocardial Inflammation ◽  
Chain Reactions ◽  
Cardiac Inflammation ◽  
Over Expression ◽  
Polymerase Chain Reactions ◽  
Tnf Α

Background: Sepsis-induced cardiac dysfunction is charactered by cardiac contractility dysfunction, myocardial inflammation and cardiac metabolism abnormal. Dysfunction of microRNAs (miRNAs, miRs) contributes to a variety of human diseases. However, their roles in sepsis-induced cardiac dysfunction are unclear. Methods and Results: Cardiac dysfunction was induced by E.coli lipopolysaccharide (LPS) administration in mice and 8 dysregulated miRNAs were identified by miRNA arrays. Among them, miR-21* was found to be increased most obviously as determined by quantitative reverse transcription polymerase chain reactions. Inhibition of miR-21* in vivo by antagomir attenuated the reduction of factional shortening (FS) and ejection fraction (EF) induced by LPS administration while forced over-expression of miR-21* in vivo by agomir accelerated LPS-induced cardiac dysfunction. Besides that, S100A8 and S100A9, two genes related to cardiac contractility were also found to be regulated in vivo by injection of miR-21* agomirs and antagomirs. Interestingly, cardiac inflammation indictors such as TNF-α and IL-6 and cardiac metabolism regulators including PPAR family, CD36, FATP, GLUT1, GLUT4, PDK4 were not changed by miR-21* in vivo. These data indicate that miR-21* controls sepsis-induced cardiac dysfunction by direct affecting cardiac contractility instead of cardiac inflammation and metabolism. SORBS2 was identified as a target gene of miR-21* and it was decreased by miR-21* agomir and increased by miR-21* antagomir in vivo. In consist with this, circulating levels of miR-21* were also increased in patients with sepsis compared with healthy controls. Conclusion: miR-21* controls sepsis-induced cardiac dysfunction by regulating SORBS2. Inhibition of miR-21* represents a novel therapeutic strategy for sepsis-induced cardiac dysfunction.

Abstract MP06: Kinin B1 Receptor Mediates Orexin System Hyperactivity In Salt-sensitive Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Rohan U Parekh ◽  
Abdel A Abdel-rahman ◽  
Srinivas Sriramula
Keyword(s):  
Radio Telemetry ◽  
Mrna Levels ◽  
Wild Type ◽  
Salt Treatment ◽  
Neurogenic Hypertension ◽  
B1 Receptor ◽  
Kinin B1 Receptor ◽  
Salt Sensitive Hypertension ◽  
The Brain

Hyperactivity of the orexin system contributes to several animal models of hypertension and enhances arginine vasopressin (AVP) release. We previously reported higher neuronal kinin B1 receptor (B1R) expression and brain AVP levels in hypertensive mice. However, the role of B1R and its interaction with orexin system in neurogenic hypertension have not been studied. In the present study, we tested the hypothesis that kinin B1R contributes to hypertension by upregulation of orexin-AVP signaling in the brain. Deoxycorticosterone acetate (DOCA)-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of wild-type (WT) male mice produced a significant increase in mean arterial pressure (MAP; radio-telemetry) (138 ±3 mmHg, n=8, p<0.01) that was blunted in B1R knockout mice (121±2 mmHg, P <0.05 vs. WT+DOCA). In WT mice, DOCA-salt, compared to vehicle, increased mRNA levels of orexin receptor 1 (2.5 fold, n=9, p<0.001), orexin receptor 2 (3 fold, n=9, p<0.001) and AVP (3 fold, n=9, p<0.01) in the hypothalamic paraventricular nucleus (PVN), and these DOCA-salt evoked effects were attenuated in B1RKO mice. Similarly, DOCA-salt evoked increases in protein expression of orexin receptor 1 and 2 in the hypothalamic PVN of WT mice were attenuated by 25±5% and 33±5% (p<0.05), respectively, in B1RKO vs WT+DOCA mice. Furthermore, DOCA-salt treatment increased plasma AVP levels in WT mice compared to vehicle treated mice (13.69±1.1 vs. 47.86±8.7 pg/ml, p<0.05), but not in B1RKO mice. Together, these data provide novel evidence that kinin B1R plays an important role in mediating DOCA-salt induced hypertension possibly via upregulating the orexin-AVP signaling in the brain.

Resveratrol protects against lipopolysaccharide-induced cardiac dysfunction by enhancing SERCA2a activity through promoting the phospholamban oligomerization

2016 ◽  
Vol 311 (4) ◽  
pp. H1051-H1062 ◽  
Author(s):  
Tao Bai ◽  
Xinyue Hu ◽  
Yang Zheng ◽  
Shudong Wang ◽  
Jian Kong ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Troponin I ◽  
Immunoblot Analysis ◽  
Related Factor ◽  
Cardiac Inflammation ◽  
Resveratrol Treatment ◽  
Lps Challenge ◽  
Factor Α ◽  
Monomer Form

The bacterial endotoxin lipopolysaccharide (LPS) is a main culprit responsible for cardiac dysfunction in sepsis. This study examined whether resveratrol could protect against LPS-induced cardiac dysfunction by improving the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. Echocardiographic parameters, cardiomyocyte contractile and Ca2+ transient properties, markers for cardiac inflammation, cell death, and oxidative stress, SERCA2a activity, and the ratios of phospholamban (PLB) monomer to oligomer were measured. Cardiac function was decreased >50% after LPS challenge (6 mg/kg for 6 h), which was improved by resveratrol. There was neither difference in plasma tumor necrosis factor-α and troponin I levels nor in infiltration of CD45+ cells in cardiac tissue between resveratrol-treated and untreated groups. In cardiomyocytes, LPS significantly decreased contractile amplitude, elongated relengthening time, diminished Ca2+ transient, reduced SERCA2a activity, and increased superoxide generation. These pathological alterations were attenuated by resveratrol treatment. Immunoblot analysis showed that LPS-treated mice had increased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and the monomer form of PLB, along with decreases in the levels of SERCA2a, the oligomer form of PLB and nuclear factor erythroid 2-related factor (Nrf-2). Resveratrol treatment upregulated SERCA2a, the oligomer form of PLB, and Nrf-2 expression and function, and downregulated MDA, 4-HNE, and the monomer form of PLB. Our data suggest that the activity of SERCA2a in endotoxemia is inhibited, possibly due to increases in the monomer form of PLB. Resveratrol protects the heart from LPS-induced injuries at least in part through promoting the oligomerization of PLB that leads to enhanced SERCA2a activity.

scholarly journals Transgenic Overexpression of the Extra-Large Gsα Variant XLαs Enhances Gsα-Mediated Responses in the Mouse Renal Proximal Tubule in Vivo

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1222-1233 ◽  
Author(s):  
Zun Liu ◽  
Hiroko Segawa ◽  
Cumhur Aydin ◽  
Monica Reyes ◽  
Reinhold G. Erben ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Immunohistochemical Analysis ◽  
Renal Proximal Tubule ◽  
Mrna Levels ◽  
Wild Type ◽  
Western Blots ◽  
Α Subunit ◽  
Exon 1 ◽  
Serum Pth

Abstract XLαs, a variant of the stimulatory G protein α-subunit (Gsα), can mediate receptor-activated cAMP generation and, thus, mimic the actions of Gsα in transfected cells. However, it remains unknown whether XLαs can act in a similar manner in vivo. We have now generated mice with ectopic transgenic expression of rat XLαs in the renal proximal tubule (rptXLαs mice), where Gsα mediates most actions of PTH. Western blots and quantitative RT-PCR showed that, while Gsα and type-1 PTH receptor levels were unaltered, protein kinase A activity and 25-hydroxyvitamin D 1-α-hydroxylase (Cyp27b1) mRNA levels were significantly higher in renal proximal tubules of rptXLαs mice than wild-type littermates. Immunohistochemical analysis of kidney sections showed that the sodium-phosphate cotransporter type 2a was modestly reduced in brush border membranes of male rptXLαs mice compared to gender-matched controls. Serum calcium, phosphorus, and 1,25 dihydroxyvitamin D were within the normal range, but serum PTH was ∼30% lower in rptXLαs mice than in controls (152 ± 16 vs. 222 ± 41 pg/ml; P &lt; 0.05). After crossing the rptXLαs mice to mice with ablation of maternal Gnas exon 1 (E1m−/+), male offspring carrying both the XLαs transgene and maternal Gnas exon 1 ablation (rptXLαs/E1m−/+) were significantly less hypocalcemic than gender-matched E1m−/+ littermates. Both E1m−/+ and rptXLαs/E1m−/+ offspring had higher serum PTH than wild-type littermates, but the degree of secondary hyperparathyroidism tended to be lower in rptXLαs/E1m−/+ mice. Hence, transgenic XLαs expression in the proximal tubule enhanced Gsα-mediated responses, indicating that XLαs can mimic Gsα in vivo.

scholarly journals Adverse perinatal environment contributes to altered cardiac development and function

2014 ◽  
Vol 306 (9) ◽  
pp. H1334-H1340 ◽  
Author(s):  
Markus Velten ◽  
Matthew W. Gorr ◽  
Dane J. Youtz ◽  
Christina Velten ◽  
Lynette K. Rogers ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Development ◽  
Calcium Transient ◽  
Growth Restriction ◽  
Calcium Handling ◽  
Lv Function ◽  
Mrna Levels ◽  
Newborn Mice

Epidemiological observations report an association between intrauterine growth restriction (IUGR) and cardiovascular diseases. Systemic maternal inflammation is the most common stress during pregnancy, leading to IUGR. We hypothesized that perinatal inflammation and hyperoxygenation induce discernible alterations in cardiomyocyte contractility and calcium signaling, causing early cardiac dysfunction. Pregnant C3H/HeN mice were injected with LPS or saline on embryonic day 16. Newborn mice were placed in 85% O2or room air (RA) for 14 days. Pups born to LPS-injected dams had reduced birth weight. Echocardiographic measurements revealed that in vivo LV function was compromised in LPS/O2mice as early as 3 days of life. Isolated cardiomyocytes from LPS/O2mice at day 14 exhibited decreased sarcomere fractional shortening, along with decreased time-to-90% peak shortening. Calcium transient amplitude was greatest in LPS/O2mice. SERCA2a mRNA and protein levels were increased and phospholamban mRNA levels were decreased in LPS/O2mice. Phosphorylation of phospholamban was increased, along with Sorcin mRNA levels in LPS/O2mice. Combined exposure to perinatal inflammation and hyperoxia resulted in growth restriction, in vivo and in vitro cardiac dysfunction, coinciding with humans and animal models of cardiac dysfunction. Expression of calcium handling proteins during the neonatal period was similar to that observed during fetal stages of development. Our data suggest that perinatal inflammation and hyperoxia exposure alter fetal development, resulting in early cardiac dysfunction.

scholarly journals miR-200c/FUT4 axis prevents the proliferation of colon cancer cells by downregulating the Wnt/β-catenin pathway

2020 ◽  
Author(s):  
Jinchun Cong ◽  
Chuanjia Yang ◽  
Zhixiu Xia ◽  
Jian Gong ◽  
Hong Zhang
Keyword(s):  
Colon Cancer ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Biological Behaviour ◽  
Western Blots ◽  
Sw480 Cells ◽  
Related Proteins

Abstract BackgroundMicroRNA(miR)-200c has been widely reported to be involved in colon cancer progress. However, the mechanisms of miR-200c in regulating tumor metastasis and growth remain to be fully elucidated. This study aimed to investigate the mechanism of miR-200c targets fucosyltransferase 4 (FUT4) on the proliferation of colon cancer.MethodsThe miR-200c and FUT4 mRNA levels in LoVo and SW480 cells were measured by real-time quantitative polymerase chain reaction. Further, miR-200c mimic, FUT4 siRNA and FUT4 mimic were transfected into cells, separately. Cell counting kit-8, plate colony formation and transwell assays were used to analyse the cells biological behaviour.. Immunofluorescence was used to analyse the Ki-67 expression Moreover, the Wnt/β-catenin pathway-related proteins were detected by western blots. A double luciferase experiment was performed to confirm the relationship between miR-200c and FUT4. In vivo, tumour growth and Wnt/β-catenin pathway-related proteins were also analysed. ResultsIn vitro, the expression of miR-200c and FUT4 were negatively correlated in LoVo and SW480 cells (correlation coefficients were -0.9046 and -0.9236, respectively). MiR-200c overexpression inhibited the proliferation, migration and invasion of LoVo and SW480 cells by downregulating FUT4. The Ki67-positive cells and Wnt/β-catenin signalling pathway-related proteins were reduced in the miR-200c overexpression and FUT4 silencing groups. A dual luciferase reporting system identified FUT4 as the target of miR-200c. The results in vivo were further confirmed the foundation of cells study.ConclusionsIn summary, miR-200c overexpression inhibits proliferation of colon cancer targeting FUT4 to downregulate the Wnt/β-catenin pathway, which promises molecular targets to inhibit metastasis for colon cancer therapy.

scholarly journals Reciprocal Regulatory Interaction between TRPV1 and Kinin B1 Receptor in a Rat Neuropathic Pain Model

2020 ◽  
Vol 21 (3) ◽  
pp. 821 ◽  
Author(s):  
Veronica Cernit ◽  
Jacques Sénécal ◽  
Rahmeh Othman ◽  
Réjean Couture
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mrna Expression ◽  
Thermal Hyperalgesia ◽  
Mrna Levels ◽  
Regulatory Interaction ◽  
B1 Receptor ◽  
Tnf Α ◽  
Kinin B1 Receptor ◽  
Sensory Fibers

Kinins are mediators of pain and inflammation and evidence suggests that the inducible kinin B1 receptor (B1R) is involved in neuropathic pain (NP). This study investigates whether B1R and TRPV1 are colocalized on nociceptors and/or astrocytes to enable regulatory interaction either directly or through the cytokine pathway (IL-1β, TNF-α) in NP. Sprague Dawley rats were subjected to unilateral partial sciatic nerve ligation (PSNL) and treated from 14 to 21 days post-PSNL with antagonists of B1R (SSR240612, 10 mg·kg−1, i.p.) or TRPV1 (SB366791, 1 mg·kg−1, i.p.). The impact of these treatments was assessed on nociceptive behavior and mRNA expression of B1R, TRPV1, TNF-α, and IL-1β. Localization on primary sensory fibers, astrocytes, and microglia was determined by immunofluorescence in the lumbar spinal cord and dorsal root ganglion (DRG). Both antagonists suppressed PSNL-induced thermal hyperalgesia, but only SB366791 blunted mechanical and cold allodynia. SSR240612 reversed PSNL-induced enhanced protein and mRNA expression of B1R and TRPV1 mRNA levels in spinal cord while SB366791 further increased B1R mRNA/protein expression. B1R and TRPV1 were found in non-peptide sensory fibers and astrocytes, and colocalized in the spinal dorsal horn and DRG, notably with IL-1β on astrocytes. IL-1β mRNA further increased under B1R or TRPV1 antagonism. Data suggest that B1R and TRPV1 contribute to thermal hyperalgesia and play a distinctive role in allodynia associated with NP. Close interaction and reciprocal regulatory mechanism are suggested between B1R and TRPV1 on astrocytes and nociceptors in NP.

PAF-induced kinin B1 receptor in vivo up-regulation: involvement of distinct kinase pathways

2007 ◽  
Vol 56 (S3) ◽  
pp. S488-S491
Author(s):  
Elizabeth S. Fernandes ◽  
Rodrigo Medeiros ◽  
Maria M. Campos ◽  
Joao B. Calixto
Keyword(s):  
B1 Receptor ◽  
Kinin B1 Receptor

Expression of kinin B1 receptor in fresh or cultured rabbit aortic smooth muscle: role of NF-κB

2002 ◽  
Vol 283 (1) ◽  
pp. H227-H237 ◽  
Author(s):  
Thierry Sabourin ◽  
Guillaume Morissette ◽  
Johanne Bouthillier ◽  
Luc Levesque ◽  
François Marceau
Keyword(s):  
Smooth Muscle ◽  
Rabbit Aorta ◽  
Aortic Tissue ◽  
Mrna Levels ◽  
Kinin B1 Receptor ◽  
Epidermal Growth ◽  
Fetal Bovine ◽  
Cultured Smooth Muscle Cells ◽  
Mrna Binding

Kinin B1receptor (B1R) expression and the importance of the transcription factor nuclear factor (NF)-κB in this process were evaluated in models based on the rabbit aorta: freshly isolated tissue (postisolation induction) and cultured smooth muscle cells (SMCs). A 3-h incubation of freshly isolated tissues determined a sharp B1R mRNA increase (RT-PCR). Coincubation of tissues with a stimulus (interleukin-1β, fetal bovine serum, epidermal growth factor, or cycloheximide) further increased mRNA levels. Cultured SMCs possessed a basal population of surface B1Rs ([3H]Lys-des-Arg9-bradykinin binding) that was upregulated by treatments with the same set of stimuli (binding, mRNA, nuclear runon). Pharmacological inhibitors of NF-κB (MG-132, BAY 11-7082, dexamethasone) or actinomycin D reduced the postisolation induction of B1Rs in fresh aortic tissue (contractility or mRNA) and the cytokine effect on cells (mRNA, binding). NF-κB may be a common mediator of various stimuli that increase B1R gene transcription in the rabbit aorta, including tissue isolation, but cycloheximide also stabilizes B1R mRNA. The SMC models faithfully mimic the in vivo situation with regard to B1R regulation.

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