Abstract 144: Post-myocardial Infarction Therapeutics Using Cardiovascular Progenitor Cells (PC) Derived from Induced Pluripotent Stem Cells (iPSC)

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yigang Wang
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Vessel Density ◽  
Protective Effects ◽  
Paracrine Factors ◽  
Beneficial Effects ◽  
The Third ◽  
Simplex Virus ◽  
Patch Group

Objective: We sought to assess the cardiac protective effects after MI of (1) PC differentiated directly into cardiomyocytes (CM) and endothelial cells (EC) to the site of injury, or (2) paracrine factors released from PC. Methods: These concepts were evaluated by using iPSC-derived PC genetically modified to express the herpes simplex virus thymidine kinase (TK) under the control of cardiomyocyte (NCX1) or endothelial cell (VE-cadherin) specific promoters. PC expressing the TK permitted ablation at the first week or the third week by iv ganciclovir (GCV). If GCV applied at the first week, but not at the third week, altered cardiac function, we would conclude that myocardial contractile recovery depends on CM and EC-derived from iPSC. If the beneficial effects on cardiac function persisted after GCV was given at the third week, we would surmise that the PC effect was via by a paracrine action. MI created by ligation of LAD, the cell patch with PC was applied to the scarred myocardium. Rats were treated with GCV at 1 or 3 weeks to ablate implanted PC. Echocardiography, vessel density, and histological analysis were used to obtain endpoints for this study. Result: In vivo : The levels of IGF-1α and VEGF released from ischemic tissues were significant higher in the cell patch group. Heart function, infarction size, and vessel density were significantly improved after cell patch treatment. However, this beneficial effect on cardiac function was completely abolished in the group given GCV at week 1, but only partially abolished in the group given GCV at week 3 compared to the untreated cell patch group. Conclusions: Taken together, these data support our conclusion that iPSC-derived cardiovascular lineages (CM and EC) contribute directly to an improved cardiac performance and attenuated remodeling, and that paracrine factors also play a supporting role in the restoration of heart function after MI.

scholarly journals e0143 In vivo study of adenvirus mediated transgenic HIF-1  and its protective effects on cardiac function in experimental myocardial infarction

Heart ◽  
2010 ◽  
Vol 96 (Suppl 3) ◽  
pp. A46-A46
Author(s):  
L. Dongye ◽  
Y. Yan ◽  
L. Yina ◽  
L. Chuang ◽  
Z. Hong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Experimental Myocardial Infarction ◽  
In Vivo Study ◽  
Protective Effects

scholarly journals Oral delivery of xenon for cardiovascular protection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xing Yin ◽  
Melanie R. Moody ◽  
Valeria Hebert ◽  
Melvin E. Klegerman ◽  
Yong-Jian Geng ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Oral Delivery ◽  
Noble Gas ◽  
Left Ventricular ◽  
Beneficial Effects ◽  
Normal Left Ventricular ◽  
Term Administration ◽  
Apoe Knockout Mice

Abstract Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-β-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.

The Indispensable Value of Clinical Trials in the Modernization of Traditional Chinese Medicine: 12 Years' Experience at CUHK and Future Perspectives

2014 ◽  
Vol 42 (03) ◽  
pp. 587-604 ◽  
Author(s):  
Willmann Liang ◽  
David T. Yew ◽  
Kam Lun Hon ◽  
Chun Kwok Wong ◽  
Timothy C. Y. Kwok ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chinese Medicine ◽  
Herbal Medicines ◽  
Chinese Herbs ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Artery Disease ◽  
The Many

The last decade has seen a wealth of information reporting the beneficial effects of Chinese herbal medicines. While a lot more studies were done using in vitro and in vivo research platforms, much fewer investigations were conducted according to evidence-based requirements in clinical settings. The Institute of Chinese Medicine at the Chinese University of Hong Kong (CUHK) has had the opportunity to collaborate with clinicians over the years to initiate and conduct dozens of clinical trials investigating and verifying the therapeutic values of Chinese herbs in selected disease conditions. Of the many disorders, we chose to focus on those that are known for their difficulties achieving perfect results with conventional treatment methods. Examples include non-healing ulcers, allergic conditions, degenerative diseases and cancer. Protective effects of the herbs in such chronic diseases as coronary artery disease and osteoporosis were also part of our focus. Even in healthy individuals and those recovering from chemotherapy, Chinese herbs could help with the immune system and were studied in our clinical trials as well. This paper aims to highlight the important findings from these clinical studies while at the same time, stressing the indispensable value of clinical trials in modernizing the use of Chinese herbs in present-day medicine.

scholarly journals Polyphenol Microbial Metabolites Exhibit Gut and Blood–Brain Barrier Permeability and Protect Murine Microglia against LPS-Induced Inflammation

Metabolites ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 78 ◽  
Author(s):  
Shelby L. Johnson ◽  
Riley D. Kirk ◽  
Nicholas A. DaSilva ◽  
Hang Ma ◽  
Navindra P. Seeram ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Circulation ◽  
Brain Barrier ◽  
Protective Effects ◽  
Microbial Metabolites ◽  
Dietary Polyphenols ◽  
Beneficial Effects ◽  
Blood Brain ◽  
Traditional Mediterranean Diet

Increasing evidence supports the beneficial effects of polyphenol-rich diets, including the traditional Mediterranean diet, for the management of cardiovascular disease, obesity and neurodegenerative diseases. However, a common concern when discussing the protective effects of polyphenol-rich diets against diseases is whether these compounds are present in systemic circulation in their intact/parent forms in order to exert their beneficial effects in vivo. Here, we explore two common classes of dietary polyphenols, namely isoflavones and lignans, and their gut microbial-derived metabolites for gut and blood–brain barrier predicted permeability, as well as protection against neuroinflammatory stimuli in murine BV-2 microglia. Polyphenol microbial metabolites (PMMs) generally showed greater permeability through artificial gut and blood–brain barriers compared to their parent compounds. The parent polyphenols and their corresponding PMMs were evaluated for protective effects against lipopolysaccharide-induced inflammation in BV-2 microglia. The lignan-derived PMMs, equol and enterolactone, exhibited protective effects against nitric oxide production, as well as against pro-inflammatory cytokines (IL-6 and TNF-α) in BV-2 microglia. Therefore, PMMs may contribute, in large part, to the beneficial effects attributed to polyphenol-rich diets, further supporting the important role of gut microbiota in human health and disease prevention.

scholarly journals Standardized Aronia melanocarpa Extract as Novel Supplement against Metabolic Syndrome: A Rat Model

2018 ◽  
Vol 20 (1) ◽  
pp. 6 ◽  
Author(s):  
Vladimir Jakoviljevic ◽  
Petar Milic ◽  
Jovana Bradic ◽  
Jovana Jeremic ◽  
Vladimir Zivkovic ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Dietary Habits ◽  
Ex Vivo ◽  
Heart Function ◽  
Standard Diet ◽  
Oral Supplementation ◽  
Beneficial Effects ◽  
Aronia Melanocarpa ◽  
Dietary Strategies

The aim of our study was to examine the effects of different dietary strategies, high-fat (HFd) or standard diet (Sd) alone or in combination with standardized oral supplementation (0.45 mL/kg/day) of Aronia melanocarpa extract (SAE) in rats with metabolic syndrome (MetS). SAE is an official product of pharmaceutical company Pharmanova (Belgrade, Serbia); however, the procedure for extraction was done by EU-Chem company (Belgrade, Serbia). Rats were divided randomly into six groups: control with Sd, control with Sd and SAE, MetS with HFd, MetS with HFd and SAE, MetS with Sd and MetS with Sd and SAE during 4 weeks. At the end of the 4-week protocol, cardiac function and liver morphology were assessed, while in the blood samples glucose, insulin, iron levels and systemic redox state were determined. Our results demonstrated that SAE had the ability to lower blood pressure and exert benefits on in vivo and ex vivo heart function. Moreover, SAE improved glucose tolerance, attenuated pathological liver alterations and oxidative stress present in MetS. Obtained beneficial effects of SAE were more prominent in combination with changing dietary habits. Promising potential of SAE supplementation alone or in combination with different dietary protocols in triggering cardioprotection should be further examined in future.

scholarly journals Reduction of cardiomyocyte S-nitrosylation by S-nitrosoglutathione reductase protects against sepsis-induced myocardial depression

2013 ◽  
Vol 304 (8) ◽  
pp. H1134-H1146 ◽  
Author(s):  
Patrick Y. Sips ◽  
Tomoya Irie ◽  
Lin Zou ◽  
Shohei Shinozaki ◽  
Michihiro Sakai ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ex Vivo ◽  
Myocardial Dysfunction ◽  
Endotoxic Shock ◽  
Protein S ◽  
Septic Cardiomyopathy ◽  
Protective Effects ◽  
Myocardial Depression ◽  
Lps Challenge

Myocardial depression is an important contributor to morbidity and mortality in septic patients. Nitric oxide (NO) plays an important role in the development of septic cardiomyopathy, but also has protective effects. Recent evidence has indicated that NO exerts many of its downstream effects on the cardiovascular system via protein S-nitrosylation, which is negatively regulated by S-nitrosoglutathione reductase (GSNOR), an enzyme promoting denitrosylation. We tested the hypothesis that reducing cardiomyocyte S-nitrosylation by increasing GSNOR activity can improve myocardial dysfunction during sepsis. Therefore, we generated mice with a cardiomyocyte-specific overexpression of GSNOR (GSNOR-CMTg mice) and subjected them to endotoxic shock. Measurements of cardiac function in vivo and ex vivo showed that GSNOR-CMTg mice had a significantly improved cardiac function after lipopolysaccharide challenge (LPS, 50 mg/kg) compared with wild-type (WT) mice. Cardiomyocytes isolated from septic GSNOR-CMTg mice showed a corresponding improvement in contractility compared with WT cells. However, systolic Ca2+ release was similarly depressed in both genotypes after LPS, indicating that GSNOR-CMTg cardiomyocytes have increased Ca2+ sensitivity during sepsis. Parameters of inflammation were equally increased in LPS-treated hearts of both genotypes, and no compensatory changes in NO synthase expression levels were found in GSNOR-overexpressing hearts before or after LPS challenge. GSNOR overexpression however significantly reduced total cardiac protein S-nitrosylation during sepsis. Taken together, our results indicate that increasing the denitrosylation capacity of cardiomyocytes protects against sepsis-induced myocardial depression. Our findings suggest that specifically reducing protein S-nitrosylation during sepsis improves cardiac function by increasing cardiac myofilament sensitivity to Ca2+.

scholarly journals Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes and Protects Diabetic Mouse Hearts by Targeting the mTOR/HIF-1α Pathway

2020 ◽  
Author(s):  
Pengbo Sun ◽  
Yipei Ding ◽  
Jingyi Luo ◽  
Jin Zhong ◽  
Weidong Xie
Keyword(s):  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mouse ◽  
Protective Effects ◽  
Pharmacological Mechanism ◽  
Beneficial Effects ◽  
Mtor Phosphorylation

Abstract BackgroundLipotoxicity plays an important role in the development of diabetic cardiomyopathy and heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significant beneficial effects on HF. However, the potential pharmacological mechanism is still unknown.MethodsIn this study, we evaluated the protective effects and mechanism of CAN in the hearts of a C57BL/6J diabetic mouse model induced by a high-fat diet/streptozotocin (HFD/STZ) for 12 weeks in vivo and using HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA) in vitro.ResultsCAN could significantly alleviate lipid accumulation and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. Furthermore, CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. In addition, CAN bound to the mammalian target of rapamycin (mTOR) and significantly inhibited mTOR phosphorylation and hypoxia inducible factor-1α (HIF-1α) expression.ConclusionCAN attenuated lipotoxicity in cardiomyocytes and protected diabetic mouse hearts by targeting the mTOR/HIF-1α pathway.

Isolated hemoperfused heart model of slaughterhouse pigs

2001 ◽  
Vol 24 (4) ◽  
pp. 215-221 ◽  
Author(s):  
D. Modersohn ◽  
S. Eddicks ◽  
C. Grosse-Siestrup ◽  
I. Ast ◽  
S. Holinski ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Animal Experiments ◽  
Laboratory Animals ◽  
Coronary Perfusion ◽  
Balloon Catheters ◽  
Wide Range ◽  
Infusion Of Norepinephrine

A model of hemoperfused slaughterhouse pighearts is described providing a wide range of applications which leads to a reduction in animal experiments. The size of a pigheart, heart rate, coronary perfusion, metabolism, etc. are more comparable to conditions in patients than those in hearts of small laboratory animals. Global heart function can be assessed either by measuring stroke volume, ejection fraction, Emaxetc. in the working model or by measuring intraventricular pressure with balloon catheters in the isovolumetric model. Regional cardiac function can be measured by sonomicrometry and ischemic and non-ischemic areas can be compared. Local metabolic changes are measurable as well with microdialysis. Cardiac function can be kept on any given functional level by infusion of norepinephrine in spite of the fact that functional parameters are lower without adrenergic drive in vitro than in vivo. Stable heart function can be maintained for several hours with only 500 to 1000 ml of blood because the blood is permanently regenerated by a special dialysis system. This model can be applied in many research projects dealing with reperfusion injuries, inotropic, antiarrhythmic or arrhythmogenic effects of certain drugs, immunological rejection, evaluation of imaging systems (NMR, echocardiography etc.) or cardiac assist devices.

Abstract 16459: Myocardial Replenishment of Tissue Inhibitor of Metalloproteinase (TIMP)-3 and TIMP4 Following Myocardial Infarction Result in Differential Protective Effects

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Abhijit Takawale ◽  
Ratnadeep Basu ◽  
Xiuhua Wang ◽  
Zamaneh Kassiri
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Response ◽  
Imaging System ◽  
Tissue Injury ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Adverse Remodeling

Introduction: The cardiomyopathy ensuing myocardial infarction (MI) results from the ischemic loss of the myocardium, impaired left ventricular (LV) dilation, eventually leading to heart failure. This is accompanied with adverse remodeling of the extracellular matrix (ECM) and disrupted balance of its regulatory proteins, particularly TIMP3 and TIMP4 that are reduced shortly after MI induction. Hypothesis: Replenishment of TIMP3 and/or TIMP4 post-MI will hinder adverse remodeling of the ECM and may also promote beneficial cellular response to limit tissue injury and cardiac dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad-hTIMP3), human TIMP4 (Ad-hTIMP4) or no-TIMP control (Ad-Null) were injected in the peri-infarct zone (5 injections/heart; 5.4x107 pfu/heart). Cardiac function was assessed by Vevo2100 ultrasound imaging system. Cellular and molecular analyses (inflammation, cell viability, angiogenesis, ECM composition) were assessed at 3 and 7 days post-MI. Results: Injection of Ad-Null had minimal effects in the post-MI dysfunction and remodeling. Ad-hTIMP3 injection exerted more beneficial effects compared to Ad-hTIMP4. Ad-TIMP3 group showed significantly better cardiac function (EF=35.49±2.52%, p<0.05), and to a lesser extent Ad-TIMP4 group (EF=28.79±1.79%) compared to Ad-Null group (EF=25.46±2.29%). Similarly, LV dilation was markedly attenuated in Ad-TIMP3 (LVEDV=77.08±6.05μL) but not in Ad-TIMP4 group (LVED=112.98±5.68 μL) compared to Ad-Null (LVEDV=112.98±7.0 μL). Inflammatory response (macrophage/neutrophil density) was not altered with Ad-TIMP treatment. Interestingly, the infarct size was smaller in Ad-TIMP3 group and even after 1wk post-MI, viable myocytes were detected in these hearts. Assessment of coronary density in the infarct and peri-infarct regions (intra-jugular fluoro-tagged lectin injection) revealed that Ad-TIMP3 promoted angiogenesis in the infarcted myocardium. Conclusions: This novel pro-angiogenic function of TIMP3 post-MI, in addition to its MMP inhibitory function, could provide additional beneficial effects in post-MI treatment.

Abstract 18382: Rna Splicing Regulated by A2bp1 is Essential for Cardiac Function in Zebrafish

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Karen S Frese ◽  
Benjamin Meder ◽  
Andreas Keller ◽  
Jan Haas ◽  
Steffen Just ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Rna Sequencing ◽  
Functional Role ◽  
Heart Function ◽  
Mrna Splicing ◽  
Complex Nature ◽  
Zebrafish Embryos ◽  
Splicing Regulator

Objective: Alternative splicing (AS) is one of the key mechanisms for the proteomic and functional diversity of eukaryotes. However, the complex nature of AS, its associated regulators and their targets are only partially understood. In the present study we investigated the transcriptomic diversity in the zebrafish heart using RNA-Sequencing and elucidated the functional role of the splicing regulator A2BP1 in vivo. Results: Using RNA-Sequencing we characterized the cardiac transcriptome of 48 hours post fertilization (hpf) old zebrafish embryos and compared the expression of genes and their isoforms to whole fish tissue. Besides the known cardiac genes, we found several previously described genes, highly expressed in cardiac tissue. The analysis of RNA-Seq data indicates that 14% of all genes expressed in the heart undergo AS by single exon-skipping/inclusion. To determine the effect of splicing factors on mRNA splicing we investigated the functional role of splicing regulator a2bp1 in vivo by using the zebrafish as a model organism. Morpholino-mediated a2bp1 knockdown in zebrafish embryos led to progressive cardiac contractile dysfunction, suggesting an important role of a2bp1 in maintenance of cardiac function. Splicing analysis revealed that loss of a2bp1 does not result in a completely splicing failure, but rather alters the splicing pattern of specific target genes. Here we identified novel spliceforms and potentialy novel targets of splicing factor a2bp1. Splice-junction blockage experiments showed that a balanced isoform expression of the targets actn3a, hug, ktn1, ptpla and camk2g is necessary for maintaining cardiac function in zebrafish. We assume, that the a2bp1-knockdown phenotype is not caused by missplicing of specific targets rather by the cumulative effect of many splicing abnormalities. Conclusion: Our study reveal a novel splicing regulator that is necessary for normal heart function. We showed that dysfunction of a2bp1 not only leads to heart failure, but show that a2bp1 mediates the splicing of different transcripts which might mediate the observed phenotype. Our results highlight the importance of balanced mRNA splicing in the heart and represents intriguing opportunities for novel therapeutic approaches.

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