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.

In vivo gene delivery of HSP70i by adenovirus and adeno-associated virus preserves contractile function in mouse heart following ischemia-reperfusion

2006 ◽  
Vol 291 (6) ◽  
pp. H2905-H2910 ◽  
Author(s):  
Darrell D. Belke ◽  
Bernd Gloss ◽  
John M. Hollander ◽  
Eric A. Swanson ◽  
Hervé Duplain ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Viral Vector ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Viral Gene ◽  
Mouse Heart ◽  
Adeno Associated Virus

Inducible heat shock protein 70 (HSP70i) has been shown to exert a protective effect in hearts subjected to ischemia-reperfusion. Although studied in heat-shocked animals and in transgenic mice that constitutively overexpress the protein, the therapeutic application of the protein in the form of a viral vector-mediated HSP70i expression has not been widely examined. Accordingly, we have examined the effects of HSP70i delivered in vivo to the left ventricular free wall of the heart via viral gene therapy in mice. The affect of virally mediated HSP70i expression in preserving cardiac function following ischemia-reperfusion was examined after short-term expression (5-day adenovirus mediated) and long-term expression (8-mo adeno-associated virus mediated) in mice by subjecting ex vivo Langendorff perfused hearts to a regime of ischemia-reperfusion. Both vectors were capable of increasing HSP70i expression in the heart, and neither vector had any effect on cardiac function during aerobic (preischemic) perfusion when compared with corresponding controls. In contrast, both adenovirus-mediated and adeno-associated virus-mediated expression of HSP70i improved the contractile recovery of the heart after 120 min of reperfusion following ischemia. This study demonstrates the feasibility of using both short- and long-term expression of virally mediated HSP70i as a therapeutic intervention against cardiac ischemia-reperfusion injury.

scholarly journals Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling

2014 ◽  
Vol 117 (6) ◽  
pp. 669-678 ◽  
Author(s):  
Ana Paula Lima-Leopoldo ◽  
André S. Leopoldo ◽  
Danielle C. T. da Silva ◽  
André F. do Nascimento ◽  
Dijon H. S. de Campos ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Function ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Standard Diet ◽  
Shortening Velocity

Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca2+) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca2+-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups ( n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), calsequestrin, L-type Ca2+ channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser16) and PLB threonine-17 phosphorylation (pPLB Thr17) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca2+. Obesity caused a reduction in cardiac pPLB Ser16 and the pPLB Ser16/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser16, but does not impair the myocardial Ca2+ entry and recapture to SR.

Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene

2013 ◽  
Vol 115 (10) ◽  
pp. 1572-1580 ◽  
Author(s):  
Vigdis Hillestad ◽  
Frank Kramer ◽  
Stefan Golz ◽  
Andreas Knorr ◽  
Kristin B. Andersson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Pressure Measurements ◽  
Human Heart Failure

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase ( Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

scholarly journals Bone Regeneration by Novel Bioactive Glasses Containing Strontium and/or Magnesium: A Preliminary In-Vivo Study

Materials ◽  
2018 ◽  
Vol 11 (11) ◽  
pp. 2223 ◽  
Author(s):  
Devis Bellucci ◽  
Valeria Cannillo ◽  
Alexandre Anesi ◽  
Roberta Salvatori ◽  
Luigi Chiarini ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Formation Processes ◽  
Complete Dissolution ◽  
In Vitro Bioactivity ◽  
Bioactive Glasses ◽  
Beneficial Effects ◽  
Glass Dissolution

In this work, a set of novel bioactive glasses have been tested in vivo in an animal model. The new compositions, characterized by an exceptional thermal stability and high in vitro bioactivity, contain strontium and/or magnesium, whose biological benefits are well documented in the literature. To simulate a long-term implant and to study the effect of the complete dissolution of glasses, samples were implanted in the mid-shaft of rabbits’ femur and analyzed 60 days after the surgery; such samples were in undersized powder form. The statistical significance with respect to the type of bioactive glass was analyzed by Kruskal–Wallis test. The results show high levels of bone remodeling, several new bone formations containing granules of calcium phosphate (sometimes with amounts of strontium and/or magnesium), and the absence of adverse effects on bone processes due to the almost complete glass dissolution. In vivo results confirming the cell culture outcomes of a previous study highlighted that these novel bioglasses had osteostimulative effect without adverse skeletal reaction, thus indicating possible beneficial effects on bone formation processes. The presence of strontium in the glasses seems to be particularly interesting.

Effect of human urotensin-II infusion on hemodynamics and cardiac function

2003 ◽  
Vol 81 (2) ◽  
pp. 125-128 ◽  
Author(s):  
Ghada S Hassan ◽  
Fazila Chouiali ◽  
Takayuki Saito ◽  
Fu Hu ◽  
Stephen A Douglas ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Urotensin Ii ◽  
Ventricular Systolic Pressure ◽  
Wide Range ◽  
Dose Dependent Decrease

Recent studies have shown that the vasoactive peptide urotensin-II (U-II) exerts a wide range of action on the cardiovascular system of various species. In the present study, we determined the in vivo effects of U-II on basal hemodynamics and cardiac function in the anesthetized intact rat. Intravenous bolus injection of human U-II resulted in a dose-dependent decrease in mean arterial pressure and left ventricular systolic pressure. Cardiac contractility represented by ±dP/dt was decreased after injection of U-II. However, there was no significant change in heart rate or diastolic pressure. The present study suggests that upregulation of myocardial U-II may contribute to impaired myocardial function in disease conditions such as congestive heart failure.Key words: urotensin-II, rat, infusion, heart.

scholarly journals Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

2020 ◽  
Author(s):  
Guo-Biao Xu ◽  
Pei-Pei Guan ◽  
Pu Wang
Keyword(s):  
Cognitive Decline ◽  
Michael Addition ◽  
Dependent Manner ◽  
Western Blots ◽  
Michael Adduct ◽  
Term Administration ◽  
Prostaglandin A1

Abstract Background: Prostaglandin (PG) A1 is a metabolic product of cyclooxygenase 2 (COX-2), which potentially involved in regulating the development and progression of Alzheimer’s disease (AD). As a cyclopentenone (cy) PG, PGA1 is characterized by the presence of a chemically reactive α, β-unsaturated carbonyl. Although PGA1 is potentially involved in regulating multiple biological processes via michael addition, its specific roles in AD remained unclear.Methods: The tauP301S transgenic (Tg) mice were employed as in vivo AD models and neuroblastoma (N) 2a cells as in vitro neuronal models. By intracerebroventricular injected (i.c.v) with PGA1, the binding proteins to PGA1 are analyzed by HPLC-MS-MS. In addition, western blots are used to determine the phosphorylation of tau in PGA1 treated Tg mice in the absence or presence of okadaic acid (OA), an inhibitor of protein phosphotase (PP) 2A. Combining a synthesis of pull down assay, immunoprecipitation, western blots and HPLC-MS-MS, PP2A scaffold subunit A alpha (PPP2R1A) was identified to be activated by directly binding on PGA1 in cysteine 377-dependent manner. Via inhibiting the hyperphosphorylation of tau, morris maze test was employed to determine the inhibitory effects of PGA1 on cognitive decline of tauP301S Tg mice.Results: By incubation with neuroblastoma (n)2a cells and pull down assay, mass spectra (MS) analysis revealed that PGA1 binds with more than 1000 proteins, among which contains the proteins of AD, especially tau protein. Moreover, short-term administration of PGA1 to tauP301S Tg mice significantly decreased the phosphorylation of tau at the sites of Thr181, Ser202 and Ser404 in a dose-dependent manner. To the reason, it’s caused by activating PPP2R1A in tauP301S Tg mice. More importantly, PGA1 has the ability to form michael adduct with PPP2R1A via its cysteine 377 motif, which is critical for the enzymatic activity of PP2A. By activating PP2A, long-term application of PGA1 to tauP301S Tg mice significantly reduced the phosphorylation of tau, which results in improving the cognitive decline of tauP301S Tg mice.Conclusion: Our data provided the first insights needed to decipher the mechanisms underlying the ameliorating effects of PGA1 on cognitive decline of tauP301S Tg mice via activating PP2A in a PPP2R1AC377-dependent Michael adducting mechanisms.

Abstract 16708: Cathelicidin Related Antimicrobial Peptide Treated Bone Marrow Derived Mononuclear Cells Improves Cardiac Function in a Mouse Model of Acute Myocardial Infarction: Potential Therapeutic Targets in Ischemic Heart Disease

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuri M Klyachkin ◽  
Prabhakara R Nagareddy ◽  
Ahmed Asfour ◽  
Shaojing Ye ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Heart Disease ◽  
Cardiac Function ◽  
Ischemic Heart Disease ◽  
Infarct Size ◽  
Left Ventricular ◽  
Ischemic Heart ◽  
In Vivo Studies ◽  
Boyden Chamber ◽  
Acute Ischemic Heart Disease

Introduction: Limited stem cell retention following intracoronary administration for ischemic heart disease has reduced the clinical efficacy of this novel therapy. Cathelicidins have been shown to prime BMMNC migration towards low gradients of SDF-1 suggesting a potential role in BMMNC retention. We sought to assess the safety and efficacy of BMMNC pre-treatment with CRAMP for treatment of acute ischemic heart disease. METHODS: BMMNCs isolated from GFP mice were incubated with recombinant CRAMP (2.5 μg/ml) or placebo for 1 hour followed by chemotaxis studies towards low levels of SDF-1 (2 ng/ml) using a Boyden chamber in vitro. During the in vivo studies, mice were randomized into 3 groups: AMI followed by injection of phosphate buffered saline (PBS), BMMNCs alone, or BMMNCs incubated with CRAMP. Scar size, survival and retention of injected BMNNCs were examined by immunohistochemistry at 5 weeks. Left ventricular function was measured by echocardiography at baseline, 48 hours, and 5 weeks after MI. Changes in infarct size between 5 days and 5 weeks after AMI was assessed by cardiac MRI utilizing delayed gadolinium enhancement. RESULTS: Treatment of BMNNCs with CRAMP enhanced their migration towards low, yet physiological, levels of SDF-1 (Fig 1A). In vivo, a greater proportion of cell survival and retention was observed in the BMNNC+CRAMP group than in the BMNNC-alone group (Fig 1B) and this was associated with higher percentage of BrdU positive cells (Fig 1C). Moreover, BMNNC+CRAMP administration led to significantly better survival, improvement of cardiac function (Fig 1D-H) and reduction in infarct size compared with other control groups (Fig 1I). CONCLUSIONS: Cathelicidins enhance BMMNC retention after intramyocardial administration for acute ischemic heart disease resulting in enhanced recovery. Therapies employing this strategy may represent an effective method for improving cardiac recovery and survival rate after AMI in human studies.

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.

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