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

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.

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

Biological Chemistry ◽

10.1515/bc.2008.070 ◽

2008 ◽

Vol 389 (6) ◽

Cited By ~ 13

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.

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Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.758670 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuxin Jia ◽

Jing Li ◽

Panpan Liu ◽

Mingdong Si ◽

Yanyu Jin ◽

...

Keyword(s):

Arsenic Trioxide ◽

Caspase 3 ◽

Troponin I ◽

Antioxidant Properties ◽

B Cell Lymphoma ◽

Flavonoid Glycoside ◽

Related Factor ◽

Treatment Groups ◽

Tnf Α ◽

Factor Α

Background: Hesperidin (HES) is a flavonoid glycoside found in the tangerine peel and has antioxidant properties. Arsenic trioxide (ATO) is an anti-tumour drug; however, its serious cardiotoxicity limits its clinical application. In addition, the protection of HES against ATO-induced cardiotoxicity has not been explored.Objective: The study aims to investigate and identify the underlying effect and mechanism of HES on ATO-induced cardiotoxicity.Methods: Fifty mice were randomly assigned to five groups. Mice were orally given HES:100 or 300 mg/kg/day concurrently and given ATO intraperitoneal injections: 7.5 mg/kg/day for 1 week. Blood and heart tissues were collected for examination. Evaluated in serum was the levels of creatine kinase (CK), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). In addition, evaluated in heart tissues were the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, cleaved-Caspase-3, p62, Kelch-like ECH-associated protein 1 (Keap1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The heart tissues were also examined for histopathology and mitochondrial ultrastructure.Results: Compared with the ATO group, the HES treatment groups reduced the levels of CK, LDH, cTnI, ROS, MDA, TNF-α, IL-6, Bax, Caspase-3, cleaved-Caspase-3 and Keap1 and enhanced the levels of SOD, GSH, CAT, Bcl-2, p62 and Nrf2.Conclusions: The results demonstrate that HES protects against ATO-induced cardiotoxicity, through inhibiting oxidative stress, and subsequent inflammation and apoptosis. The underlying results are closely related to the regulation of the p62-Keap1-Nrf2 signalling pathway.

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Role of TFEB Mediated Autophagy, Oxidative Stress, Inflammation, and Cell Death in Endotoxin Induced Myocardial Toxicity of Young and Aged Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/5380319 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 20

Author(s):

Fang Li ◽

Fangfang Lang ◽

Huilin Zhang ◽

Liangdong Xu ◽

Yidan Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Cardiac Dysfunction ◽

Myocardial Injury ◽

Troponin I ◽

Left Ventricular ◽

Aged Mice ◽

Lps Challenge ◽

Age Dependent ◽

Young Mice

Elderly patients are susceptible to sepsis. LPS induced myocardial injury is a widely used animal model to assess sepsis induced cardiac dysfunction. The age dependent mechanisms behind sepsis susceptibility were not studied. We analyzed age associated changes to cardiac function, cell death, inflammation, oxidative stress, and autophagy in LPS induced myocardial injury. Both young and aged C57BL/6 mice were used for LPS administration. The results demonstrated that LPS induced more cardiac injury (creatine kinase, lactate dehydrogenase, troponin I, and cardiac myosin-light chains 1), cardiac dysfunction (left ventricular inner dimension, LVID, and ejection fraction (EF)), cell death, inflammation, and oxidative stress in aged mice compared to young mice. However, a significant age dependent decline in autophagy was observed. Translocation of Transcription Factor EB (TFEB) to nucleus and formation of LC3-II were significantly reduced in LPS administered aged mice compared to young ones. In addition to that, downstream effector of TFEB, LAMP-1, was induced in response to LPS challenge in young mice. The present study newly demonstrates that TFEB mediated autophagy is crucial for protection against LPS induced myocardial injury particularly in aging senescent heart. Targeting this autophagy-oxidative stress-inflammation-cell death axis may provide a novel therapeutic strategy for cardioprotection in the elderly.

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ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.732952 ◽

2021 ◽

Vol 9 ◽

Author(s):

Joseph Adu-Amankwaah ◽

Gabriel Komla Adzika ◽

Adebayo Oluwafemi Adekunle ◽

Marie Louise Ndzie Noah ◽

Richard Mprah ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Dysfunction ◽

Limited Information ◽

Cardiac Inflammation ◽

Persistent Inflammation ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Interleukin 6 Receptor ◽

Factor Α ◽

Necrosis Factor

Heart failure development is characterized by persistent inflammation and progressive fibrosis owing to chronic catecholamine stress. In a chronic stress state, elevated catecholamines result in the overstimulation of beta-adrenergic receptors (βARs), specifically β2-AR coupling with Gαi protein. Gαi signaling increases the activation of receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs). Phosphorylation by these kinases is a common way to positively regulate the catalytic activity of A Disintegrin and Metalloprotease 17 (ADAM17), a metalloprotease that has grown much attention in recent years and has emerged as a chief regulatory hub in inflammation, fibrosis, and immunity due to its vital proteolytic activity. ADAM17 cleaves and activates proinflammatory cytokines and fibrotic factors that enhance cardiac dysfunction via inflammation and fibrosis. However, there is limited information on the cardiovascular aspect of ADAM17, especially in heart failure. Hence, this concise review provides a comprehensive insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. This review highlights the inflammatory and fibrotic roles of ADAM17’s substrates; Tumor Necrosis Factor α (TNFα), soluble interleukin-6 receptor (sIL-6R), and amphiregulin (AREG). Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed.

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Resveratrol Protects Cardiac Tissue in Experimental Malignant Hypertension Due to Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22095006 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5006

Author(s):

Jelica Grujić-Milanović ◽

Vesna Jaćević ◽

Zoran Miloradović ◽

Djurdjica Jovović ◽

Ivica Milosavljević ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Diseases ◽

Cardiac Tissue ◽

Morphological Changes ◽

Chronic Administration ◽

Heart Tissue ◽

Severe Form ◽

Malignant Hypertension ◽

Experimental Hypertension ◽

Resveratrol Treatment

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

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Cardiac biomarkers in acute respiratory distress syndrome: a systematic review and meta-analysis

Journal of Intensive Care ◽

10.1186/s40560-021-00548-6 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Dilip Jayasimhan ◽

Simon Foster ◽

Catherina L. Chang ◽

Robert J. Hancox

Keyword(s):

Systematic Review ◽

Acute Respiratory Distress Syndrome ◽

Intensive Care ◽

Cardiac Dysfunction ◽

Distress Syndrome ◽

Troponin I ◽

Meta Analysis ◽

Cardiac Injury ◽

Cardiac Biomarkers ◽

Risk Of Death

Abstract Background Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in the intensive care unit. Biochemical markers of cardiac dysfunction are associated with high mortality in many respiratory conditions. The aim of this systematic review is to examine the link between elevated biomarkers of cardiac dysfunction in ARDS and mortality. Methods A systematic review of MEDLINE, EMBASE, Web of Science and CENTRAL databases was performed. We included studies of adult intensive care patients with ARDS that reported the risk of death in relation to a measured biomarker of cardiac dysfunction. The primary outcome of interest was mortality up to 60 days. A random-effects model was used for pooled estimates. Funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square tests and I2 tests were used to assess heterogeneity. Results Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Biomarkers of cardiac stretch included NT-ProBNP (nine studies) and BNP (six studies). Biomarkers of cardiac injury included Troponin-T (two studies), Troponin-I (one study) and High-Sensitivity-Troponin-I (three studies). Three studies assessed multiple cardiac biomarkers. High levels of NT-proBNP and BNP were associated with a higher risk of death up to 60 days (unadjusted OR 8.98; CI 4.15-19.43; p<0.00001). This association persisted after adjustment for age and illness severity. Biomarkers of cardiac injury were also associated with higher mortality, but this association was not statistically significant (unadjusted OR 2.21; CI 0.94-5.16; p= 0.07). Conclusion Biomarkers of cardiac stretch are associated with increased mortality in ARDS.

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Nepetoidin B from Salvia plebeia R. Br. Inhibits Inflammation by Modulating the NF-κB and Nrf2/HO-1 Signaling Pathways in Macrophage Cells

Antioxidants ◽

10.3390/antiox10081208 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1208

Author(s):

Mina Kim ◽

Ji Yeong Kim ◽

Hee Sun Yang ◽

Jeong-Sook Choe ◽

In Guk Hwang

Keyword(s):

Defense Mechanisms ◽

Inflammatory Diseases ◽

Cell Damage ◽

Treated Group ◽

Raw 264.7 Cells ◽

Resonance Spectroscopy ◽

Raw 264.7 ◽

Related Factor ◽

Anti Inflammatory ◽

Factor Α

Salvia plebeia has been used to treat a variety of inflammatory diseases, as well as colds and bronchitis. Macrophages have antioxidant defense mechanisms to cope with the intracellular reactive oxygen species (ROS) produced as part of the immune response. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway in inflamed macrophages is an appealing target due to its protective effect against ROS-induced cell damage. In this study, nepetoidin B (NeB) was first isolated from S. plebeia and identified by nuclear magnetic resonance spectroscopy. NeB reduced pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β) in LPS-activated RAW 264.7 cells by inhibiting the NF-κB signaling pathway. In the NeB-treated group, catalase and superoxide dismutase levels were significantly higher, and ROS expression decreased. By activating Nrf2 signaling, NeB enhanced HO-1 expression. Furthermore, when the cells were pretreated with tin protoporphyrin (an HO-1 inhibitor), the anti-inflammatory effects of NeB were reduced. Therefore, NeB may activate the Nrf2/ HO-1 pathway. These results reveal the NeB isolated from S. plebeia exerts anti-inflammatory effects by modulating NF-κB signaling and activating the Nrf2/HO-1 pathway in LPS-stimulated RAW 264.7 cells.

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Application potential of three-dimensional silk fibroin scaffold using mesenchymal stem cells for cardiac regeneration

Journal of Biomaterials Applications ◽

10.1177/08853282211018529 ◽

2021 ◽

pp. 088532822110185

Author(s):

Yuksel Cetin ◽

Merve G Sahin ◽

Fatma N Kok

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Silk Fibroin ◽

Cardiac Tissue ◽

Troponin I ◽

Cardiac Tissue Engineering ◽

Swelling Ratio ◽

Differentiation Potential ◽

Cardiomyogenic Differentiation

Cardiac tissue engineering focusing on biomaterial scaffolds incorporating cells from different sources has been explored to regenerate or repair damaged area as a lifesaving approach.The aim of this study was to evaluate the cardiomyocyte differentiation potential of human adipose mesenchymal stem cells (hAD-MSCs) as an alternative cell source on silk fibroin (SF) scaffolds for cardiac tissue engineering. The change in surface morphology of SF scaffolds depending on SF concentration (1–6%, w/v) and increase in their porosity upon application of unidirectional freezing were visualized by scanning electron microscopy (SEM). Swelling ratio was found to increase 2.4 fold when SF amount was decreased from 4% to 2%. To avoid excessive swelling, 4% SF scaffold with swelling ratio of 10% (w/w) was chosen for further studies.Biodegradation rate of SF scaffolds depended on enzymatic activity was found to be 75% weight loss of SF scaffolds at the day 14. The phenotype of hAD-MSCs and their multi-linage potential into chondrocytes, osteocytes, and adipocytes were shown by flow cytometry and immunohistochemical staining, respectively.The viability of hAD-MSCs on 3D SF scaffolds was determined as 90%, 118%, and 138% after 1, 7, and 14 days, respectively. The use of 3D SF scaffolds was associated with increased production of cardiomyogenic biomarkers: α-actinin, troponin I, connexin 43, and myosin heavy chain. The fabricated 3D SF scaffolds were proved to sustain hAD-MSCs proliferation and cardiomyogenic differentiation therefore, hAD-MSCs on 3D SF scaffolds may useful tool to regenerate or repair damaged area using cardiac tissue engineering techniques.

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Galangin Resolves Cardiometabolic Disorders through Modulation of AdipoR1, COX-2, and NF-κB Expression in Rats Fed a High-Fat Diet

Antioxidants ◽

10.3390/antiox10050769 ◽

2021 ◽

Vol 10 (5) ◽

pp. 769

Author(s):

Patoomporn Prasatthong ◽

Sariya Meephat ◽

Siwayu Rattanakanokchai ◽

Juthamas Khamseekaew ◽

Sarawoot Bunbupha ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Tissue ◽

Sprague Dawley ◽

High Fat ◽

Impaired Liver Function ◽

Impaired Liver ◽

Cardiometabolic Disorders ◽

Cox 2 ◽

Factor Α ◽

And Oxidative Stress

Galangin is a natural flavonoid. In this study, we evaluated whether galangin could alleviate signs of metabolic syndrome (MS) and cardiac abnormalities in rats receiving a high-fat (HF) diet. Male Sprague–Dawley rats were given an HF diet plus 15% fructose for four months, and they were fed with galangin (25 or 50 mg/kg), metformin (100 mg/kg), or a vehicle for the last four weeks. The MS rats exhibited signs of MS, hypertrophy of adipocytes, impaired liver function, and cardiac dysfunction and remodeling. These abnormalities were alleviated by galangin (p < 0.05). Interleukin-6 and tumor necrosis factor-α concentrations and expression were high in the plasma and cardiac tissue in the MS rats, and these markers were suppressed by galangin (p < 0.05). These treatments also alleviated the low levels of adiponectin and oxidative stress induced by an HF diet in rats. The downregulation of adiponectin receptor 1 (AdipoR1) and cyclooxygenase-2 (COX-2) and the upregulation of nuclear factor kappa B (NF-κB) expression were recovered in the galangin-treated groups. Metformin produced similar effects to galangin. In conclusion, galangin reduced cardiometabolic disorders in MS rats. These effects might be linked to the suppression of inflammation and oxidative stress and the restoration of AdipoR1, COX-2, and NF-κB expression.

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