Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity

Zhu, Huolan; Gao, Yan; Zhu, Shunming; Cui, Qianwei; Du, Jie

doi:10.12659/msm.907449

Cited by 35 publications

(18 citation statements)

References 33 publications

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“…Even though patients divided according to the soluble α -Klotho level tertiles had similar demographic and pharmacotherapy characteristics, IS types, and coexisting diseases (except obesity), both the severity of IS and long-term (12, 24, and 36 months) outcomes were similar. Our findings are not in line with experimental model described by Zhu et al [ 3 ], showing the inhibition of postischemia neuronal loss by the overexpression of Klotho. Moreover, in the study performed by Lee et al [ 21 ], patients with lower soluble α -Klotho levels had greater cerebral infarction volume and neurological deficit, and this fact seems to explain the worse 3-month outcome in their cohort.…”

Section: Discussioncontrasting

confidence: 99%

“…Klotho, a transmembrane protein, is predominantly but not exclusively expressed in the distal tubular cells of the kidney, parathyroid glands, and choroid plexus of the brain. Its soluble form is created mostly by proteolytic shedding of the extracellular part of the full-length Klotho [ 3 ]. In the kidney, α -Klotho plays a role of a coreceptor for fibroblast growth factor 23 (FGF23) associated with arteriosclerosis prevention [ 4 ] and is involved in phosphorus excretion [ 5 ], whereas soluble α -Klotho participates in the regulation of endothelial nitric oxidase synthase (eNOS) activity and calcium channel transient receptor potential vanilloid 5 (TRPV5) in calcium homeostasis [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Higher Serum-Soluble α-Klotho Level Does Not Predict Longer Survival after Stroke

Adamska-Tomaszewska

Wajda²,

Wyskida

et al. 2020

BioMed Research International

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Aims and Scope. Ischemic stroke (IS) is one of the main causes of death and disability worldwide. It has been suggested that the Klotho protein, playing a preventive role in the development of atherosclerosis, may be associated with a better recovery after IS. Therefore, the aim of this study was to analyze whether Klotho serum levels indeed correlate with long-term IS outcomes, such as overall survival (OS) and stroke-free survival (SFS). Material and Methods. The study group consisted of 217 patients with onset of IS symptoms within 24 hours before admission to the hospital. IS was diagnosed using the WHO criteria and radiology imaging. ELISA kits were used to assess soluble α-Klotho and fibroblast growth factor 23 serum levels. Results. There were 5 recurrent strokes and 89 deaths during the 36-month follow-up. Even though no significant differences in OS and SFS between soluble α-Klotho level tertile groups were recorded, unexpectedly, OS and SFS were highest in patients with the lowest soluble α-Klotho concentrations. Moreover, the Cox proportional models adjusted for established risk factors, kidney function, and the severity of stroke revealed that each 100 pg/mL increase in soluble α-Klotho levels was associated with decreased OS ( HR = 0.951 (0.908–0.995), p < 0.05 ) and SFS ( HR = 0.949 (0.908–0.993), p < 0.05 ). In addition, the α-Klotho to iFGF23 index was predicting neither OS nor SFS. Conclusion. Soluble α-Klotho levels in serum were not related to the severity of neurological deficits and long-term outcomes in patients with IS. No neuroprotective effect of soluble α-Klotho levels in patients with IS was demonstrated.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Higher Serum-Soluble α-Klotho Level Does Not Predict Longer Survival after Stroke

Adamska-Tomaszewska

Wajda²,

Wyskida

et al. 2020

BioMed Research International

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“…Echocardiographic measures of RV function have always been limited owing to the complex geometry of the right ventricle, thus it is possible that there may have been improvement in the RV function, which was not accounted for by TAPSE. Our current finding of improved LV function is nonetheless in keeping with other investigators who demonstrated improved cardiac function in mice with doxorubicin-induced cardiac injury following Klotho administration 53 .…”

Section: Discussionsupporting

confidence: 92%

Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants

Batlahally

Franklin

Damianos

et al. 2020

Sci Rep

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preterm infants with bronchopulmonary dysplasia (BpD) and pulmonary hypertension (pH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BpD-pH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. in experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% o 2) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BpD or BpD-pH had decreased cord Klotho levels. early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function. Together, these findings have important implications as they suggest that perinatal Klotho deficiency contributes to BPD-PH risk and strategies that preserve Klotho levels, may improve long-term cardiopulmonary outcomes in preterm infants. Bronchopulmonary dysplasia (BPD) is a multi-factorial disease which affects premature infants 1. It is characterized by alterations in lung development, vascular remodeling and lung dysfunction that range the spectrum of mild to severe and even fatal disease. Preterm infants with BPD often grow poorly 2 and in the most severe cases develop pulmonary hypertension (PH) 3 , and myocardial dysfunction 4,5. According to data from the National Institute of Child Health and Human Development, during the years 2003 to 2007, the incidence of BPD in infants less than 29 weeks gestational age was 42% 6 with an increasing trend over the past 10 years 7. Not only does BPD increase infant mortality but survivors have cardiopulmonary dysfunction extending long into adulthood 8. Various prenatal and postnatal factors contribute to the development of BPD and its sequelae. Infants with placental vascular malperfusion are at an increased risk for BPD and PH 9 while hyperoxia 10 , infection 11 and poor

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“…In an oxidative damage model, klotho was reported to attenuate oxidant-induced alveolar epithelial cell apoptosis and mitochondrial DNA damage ( 29 ). Moreover, klotho was also found to suppress ROS-induced apoptosis to improve cardiac function ( 30 ). In a stress-induced cardiac injury model, klotho inhibited cardiomyocyte apoptosis partly by suppressing the activation of the p38 and JNK pathways ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

Klotho overexpression suppresses apoptosis by regulating the Hsp70/Akt/Bad pathway in H9c2(2-1) cells

Su²,

et al. 2021

Exp Ther Med

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Early reperfusion is the most effective and important treatment for acute myocardial infarction. However, reperfusion therapy often leads to a certain degree of myocardial damage. The aim of the present study was to identify the role of klotho, and the molecular mechanism underlying its effects, in myocardial damage using a model of myocardial hypoxia injury. Hypoxia/reoxygenation (H/R) was used to mimic ischemia/reperfusion (I/R) injury in vitro . The expression and distribution of klotho in H9c2(2-1) cells was observed by fluorogenic scanning, and the apoptotic rate was determined by Annexin V-FITC/propidium iodide dual staining. Cell viability was determined by MTT assay, and caspase-3, cleaved caspase-3, Bcl-2, Bax, heat shock protein (Hsp) 70 and Akt levels were assessed by western blotting. A lactate dehydrogenase test was performed to determine the degree of H9c2(2-1) cell damage. The results revealed that klotho was primarily located in the cytoplasm of H9c2(2-1) cells. Klotho overexpression markedly suppressed H/R-induced H9c2(2-1) cell apoptosis. Furthermore, cell viability increased, and injury decreased in response to klotho. Klotho also suppressed the activation of caspase-3, upregulated Bcl2 and decreased Bax levels following H/R injury, as well as alleviating H/R injury by upregulating the expression of Hsp70 and increasing the levels of phosphorylated (p-)Akt and Bad. In conclusion, these results indicate that klotho suppressed H/R-induced H9c2(2-1) cell apoptosis by regulating the levels of Hsp70, p-Akt and p-Bad, which suggest that klotho could be a novel agent for the treatment of coronary disease.

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Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity

Cited by 35 publications

References 33 publications

Higher Serum-Soluble α-Klotho Level Does Not Predict Longer Survival after Stroke

Higher Serum-Soluble α-Klotho Level Does Not Predict Longer Survival after Stroke

Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants

Klotho overexpression suppresses apoptosis by regulating the Hsp70/Akt/Bad pathway in H9c2(2-1) cells

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