scholarly journals A Sphingosine Kinase Form 2 Knockout Sensitizes Mouse Myocardium to Ischemia/Reoxygenation Injury and Diminishes Responsiveness to Ischemic Preconditioning

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Donald A. Vessey ◽  
Luyi Li ◽  
Zhu-Qiu Jin ◽  
Michael Kelley ◽  
Norman Honbo ◽  
...  
Keyword(s):  
Protective Effect ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Sphingosine Kinase ◽  
Left Ventricular ◽  
Cardiac Damage ◽  
Sphingosine 1 Phosphate ◽  
Reoxygenation Injury ◽  
Developed Pressure

Sphingosine kinase (SphK) exhibits two isoforms, SphK1 and SphK2. Both forms catalyze the synthesis of sphingosine 1-phosphate (S1P), a sphingolipid involved in ischemic preconditioning (IPC). Since the ratio of SphK1 : SphK2 changes dramatically with aging, it is important to assess the role of SphK2 in IR injury and IPC. Langendorff mouse hearts were subjected to IR (30 min equilibration, 50 min global ischemia, and 40 min reperfusion). IPC consisted of 2 min of ischemia and 2 min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), ± dP/dtmax, and heart rate between SphK2 null (KO) and wild-type (WT) hearts. In KO hearts, SphK2 activity was undetectable, and SphK1 activity was unchanged compared to WT. Total SphK activity was reduced by 53%. SphK2 KO hearts subjected to IR exhibited significantly more cardiac damage (% infarct size) compared with WT (% infarct size); postischemic recovery of LVDP was lower in KO hearts. IPC exerted cardioprotection in WT hearts. The protective effect of IPC against IR was diminished in KO hearts which had much higher infarction sizes (%) compared to the IPC/IR group in control hearts (%). Western analysis revealed that KO hearts had substantial levels of phosphorylated p38 which could predispose the heart to IR injury. Thus, deletion of the SphK2 gene sensitizes the myocardium to IR injury and diminishes the protective effect of IPC.

scholarly journals Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning

2009 ◽  
Vol 297 (4) ◽  
pp. H1429-H1435 ◽  
Author(s):  
Donald A. Vessey ◽  
Luyi Li ◽  
Norman Honbo ◽  
Joel S. Karliner
Keyword(s):  
Infarct Size ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Left Ventricular ◽  
Rat Hearts ◽  
Sphingosine 1 Phosphate ◽  
Adenosine Antagonist ◽  
Specific Antagonist ◽  
Reoxygenation Injury ◽  
Developed Pressure

Exogenous sphingosine 1-phosphate (S1P) is an effective cardioprotectant against ischemic injury. We have investigated the hypothesis that S1P is also an important endogenous cardioprotectant released during both ischemic preconditioning (IPC) and ischemic postconditioning (IPOST). IPC of ex vivo rat hearts was instituted by two cycles of 3 min ischemia-5 min reperfusion prior to 40 min of index ischemia and then 40 min of reperfusion. IPC resulted in 70% recovery of left ventricular developed pressure (LVDP) upon reperfusion and a small infarct size (10%). VPC23019 (VPC), a specific antagonist of S1P1 and 3 G protein-coupled receptors (GPCRs), when present during preconditioning blocked protection afforded by two cycles of IPC. VPC also blocked preconditioning of isolated rat cardiac myocytes subjected to hypoxia-reoxygenation injury. Increased release of S1P from myocytes in response to IPC was also demonstrated. These data indicate that S1P is released from myocytes in response to IPC and protects by binding to S1P GPCRs. In the ex vivo heart, if a third cycle of IPC was added to increase release of endogenous mediators, then the need for any individual mediator (e.g., S1P) was diminished and VPC had little effect. The adenosine antagonist 8-( p-sulfophenyl)-theophylline (8-SPT) likewise inhibited protection by two cycles but not three cycles of IPC, but VPC plus 8-SPT inhibited protection by three cycles of IPC. Similar to IPC, IPOST induced by four postindex ischemia cycles of 15 s reperfusion-15 s ischemia resulted in 66% recovery of LVDP and a 7% infarct size. When VPC was present during postconditioning and reperfusion, LVDP only recovered by 26% and the infarct size increased to 27%. Adding an additional cycle of IPOST reduced the inhibitory effect of VPC and 8-SPT individually, but not their combined effect. These studies reveal that S1P is an important mediator of both IPC and IPOST that is released along with adenosine during each cycle of IPC or IPOST.

Lipoxygenase metabolism of arachidonic acid in ischemic preconditioning and PKC-induced protection in heart

1999 ◽  
Vol 276 (6) ◽  
pp. H2094-H2101 ◽  
Author(s):  
Weina Chen ◽  
Wayne Glasgow ◽  
Elizabeth Murphy ◽  
Charles Steenbergen
Keyword(s):  
Arachidonic Acid ◽  
Protective Effect ◽  
Ischemic Preconditioning ◽  
Rabbit Heart ◽  
Left Ventricular ◽  
Arachidonic Acid Metabolism ◽  
Developed Pressure ◽  
12 Lipoxygenase ◽  
Hydroperoxyeicosatetraenoic Acid ◽  
Pkc Activation

We tested the hypothesis that activation of the 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism contributes to the protective effect of protein kinase C (PKC) activation and ischemic preconditioning (PC), and we report, in perfused rat heart, that both PC and the PKC activator 1,2-dioctanoyl- sn-glycerol (DOG) confer a similar protective effect and stimulate a comparable accumulation of 12-LO metabolites. The 12-LO product, 12( S)-hydroxyeicosatetraenoic acid [12( S)-HETE], was increased in DOG-treated (22.8 ± 4.4 ng/g wet wt) and PC hearts (26.8 ± 5.5 ng/g wet wt) compared with control (13.8 ± 2.1 ng/g wet wt, P < 0.05), and this increase was blocked by 12-LO or PKC inhibitors. Both DOG pretreatment and PC improved recovery of left ventricular developed pressure (LVDP) nearly twofold after 20 min of ischemia; this improvement was blocked by 12-LO inhibitors and was mimicked by infusion of 12-hydroperoxyeicosatetraenoic acid [12( S)-HpETE; 67 ± 6% recovery of LVDP vs. 35 ± 3% for untreated hearts]. Also, the protection afforded by 12( S)-HpETE, as well as by PC, was attenuated by the K+-channel blocker 5-hydroxydecanoate, suggesting that the downstream mechanisms of 12( S)-HpETE-mediated protection are similar to PC. Furthermore, PC stimulates 12-LO metabolism in perfused rabbit heart, and 12-LO inhibition blocks PC-induced cardioprotection. Thus the data suggest that 12-LO metabolism plays an important role in cardioprotection.

Acute inhibition of monoamine oxidase and ischemic preconditioning in isolated rat hearts: interference with postischemic functional recovery but no effect on infarct size reduction

2015 ◽  
Vol 93 (9) ◽  
pp. 819-825 ◽  
Author(s):  
Maria D. Dănilă ◽  
Andreea I. Privistirescu ◽  
Silvia N. Mirica ◽  
Adrian Sturza ◽  
Valentin Ordodi ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Left Ventricular ◽  
Mao Inhibitors ◽  
Rat Hearts ◽  
System Generation ◽  
Infarct Size Reduction ◽  
Developed Pressure ◽  
Isolated Rat

Monoamine oxidases (MAOs) have recently emerged as important mitochondrial sources of oxidative stress in the cardiovascular system. Generation of reactive oxygen species during the brief episodes of ischemic preconditioning (IPC) is responsible for the cardioprotection at reperfusion. The aim of this study was to assess the effects of two MAO inhibitors (clorgyline and pargyline) on the IPC-related protection in isolated rat hearts. Animals subjected to 30 min global ischemia and 120 min reperfusion were assigned to the following groups: (i) Control, no additional intervention; (ii) IPC, 3 cycles of 5 min ischemia and 5 min reperfusion before the index ischemia; (iii) IPC-clorgyline, IPC protocol bracketed for 5 min with clorgyline (50 μmol/L); (iv) IPC-pargyline, IPC protocol bracketed for 5 min with pargyline (0.5 mmol/L). The postischemic functional recovery was assessed by the left ventricular developed pressure (LVDP) and the indices of contractility (+dLVP/dt max) and relaxation (–dLVP/dt max). Infarct size (IS) was quantified by TTC staining. In both genders, IPC significantly improved functional recovery that was further enhanced in the presence of either clorgyline or pargyline. IS reduction was comparable among all the preconditioned groups, regardless of the presence of MAO inhibitors. In isolated rat hearts, acute inhibition of MAOs potentiates the IPC-induced postischemic functional recovery without interfering with the anti-necrotic protection.

scholarly journals Sphingosine Protects Aging Hearts from Ischemia/Reperfusion Injury: Superiority to Sphingosine 1-Phosphate and Ischemic Pre- and Post-Conditioning

2009 ◽  
Vol 2 (3) ◽  
pp. 146-151 ◽  
Author(s):  
Donald A. Vessey ◽  
Michael Kelley ◽  
Luyi Li ◽  
Yong Huang
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Diminished Capacity ◽  
Sphingosine 1 Phosphate ◽  
Phosphate Treatment ◽  
Developed Pressure ◽  
Large Infarct

Aging hearts are known to have diminished capacity to be protected against reoxygenation ischemia/reperfusion (IR) injury provided by various cardioprotective regimens. In search of a more successful regimen, we have studied the response of aged hearts to preconditioning (PC) and postconditioning (POST) elicited by sphingosine or sphingosine 1-phosphate treatment.An ex vivo rat heart model was used to study the ability of PC and POST to protect old hearts (27 month) against I/R injury generated by 40 minutes (min) of index ischemia followed by 40 min of reperfusion. The response to ischemic PC was reduced in 27 month old hearts relative to 3–6 month (young) hearts as noted by a poor recovery of left ventricular developed pressure (LVDP) upon reperfusion (45% vs. 74% in young hearts) and a large infarct size after 40 min of reperfusion (37% versus 8% in young hearts). PC with sphingosine 1-phosphate (S1P) was also poor in old hearts yielding only 49% recovery of LVDP and a 27% infarct size. In contrast, PC with sphingosine was unaffected by aging; the 78% recovery of LVDP and 8% infarct size were not different from young hearts. Ischemic POST was less affected by aging than ischemic PC, but the old hearts still experienced infarct sizes of 28%. POST of old hearts with S1P was also associated with a substantial infarct size (24%). However, POST of old hearts with sphingosine was superior to the other forms of POST in that it reduced the infarct size to 12%. S1P levels were found to be lower in old hearts which may contribute to the decreased effectiveness of ischemic PC and POST. Further, phospho-Akt levels and distribution were altered in response to cardioprotection in the old hearts. In conclusion, POST was less affected by aging than PC; and sphingosine is a uniquely effective agent for both PC and POST of aging hearts.

Protective Effect of Swertiamarin on Myocardial Injury Through Activation of Nrf2/HO-1 Pathway in Heart Failure Model of Rats

2020 ◽  
Vol 18 (3) ◽  
pp. 260-265
Author(s):  
Xu Lin ◽  
Zheng Xiaojun ◽  
Lv Heng ◽  
Mo Yipeng ◽  
Tong Hong
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Protective Effect ◽  
Infarct Size ◽  
Rat Model ◽  
Left Ventricular ◽  
Related Factor ◽  
Nuclear Factor ◽  
Internal Dimension

The purpose of this study was to evaluate the protective effect of swertiamarin on heart failure. To this end, a rat model of heart failure was established via left coronary artery ligation. Infarct size of heart tissues was determined using triphenyl tetrazolium chloride staining. Echocardiography was performed to evaluate cardiac function by the determination of ejection fraction, left ventricular internal dimension in diastole and left ventricular internal dimension in systole. The effect of swertiamarin on oxidative stress was evaluated via enzyme-linked immunosorbent assay. The mechanism was evaluated using western blot. Administration of swertiamarin reduced the infarct size of heart tissues in rat models with heart failure. Moreover, swertiamarin treatment ameliorated the cardiac function, increased ejection fraction and fractional shortening, decreased left ventricular internal dimension in diastole and left ventricular internal dimension in systole. Swertiamarin improved oxidative stress with reduced malondialdehyde, while increased superoxide dismutase, glutathione, and GSH peroxidase. Furthermore, nuclear-factor erythroid 2-related factor 2, heme oxygenase and NAD(P)H dehydrogenase (quinone 1) were elevated by swertiamarin treatment in heart tissues of rat model with heart failure. Swertiamarin alleviated heart failure through suppression of oxidative stress response via nuclear-factor erythroid 2-related factor 2/heme oxygenase-1 pathway providing a novel therapeutic strategy for heart failure.

Ischemic preconditioning in rats: role of mitochondrial KATP channel in preservation of mitochondrial function

2000 ◽  
Vol 278 (1) ◽  
pp. H305-H312 ◽  
Author(s):  
Ryan M. Fryer ◽  
Janis T. Eells ◽  
Anna K. Hsu ◽  
Michele M. Henry ◽  
Garrett J. Gross
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Area At Risk ◽  
Selective Antagonist ◽  
Mitochondrial Katp Channel

We examined the role of the sarcolemmal and mitochondrial KATPchannels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 ± 1%) versus control (56 ± 1%). The sarcolemmal KATP channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial KATP channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 ± 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 ± 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 ± 0.30 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 ± 0.06 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. IPC significantly increased ATP synthesis to 1.86 ± 0.23 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 ± 0.15 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1). These data are consistent with the notion that inhibition of mitochondrial KATPchannels attenuates IPC by reducing IPC-induced protection of mitochondrial function.

Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia

1997 ◽  
Vol 272 (3) ◽  
pp. H1333-H1341 ◽  
Author(s):  
M. X. He ◽  
S. Wang ◽  
H. F. Downey
Keyword(s):  
Inorganic Phosphate ◽  
Contractile Force ◽  
Left Ventricular ◽  
Resonance Spectroscopy ◽  
Rat Hearts ◽  
Initial Control ◽  
Myocardial Contractile Force ◽  
Myocardial Contractile ◽  
Developed Pressure

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.

Transgenic overexpression of cardiac A1adenosine receptors mimics ischemic preconditioning

2000 ◽  
Vol 279 (3) ◽  
pp. H1071-H1078 ◽  
Author(s):  
R. Ray Morrison ◽  
Rachael Jones ◽  
Anne M. Byford ◽  
Alyssa R. Stell ◽  
Jason Peart ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Adenosine Receptors ◽  
Myocardial Function ◽  
Wild Type ◽  
Beneficial Effects ◽  
Pressure Development ◽  
Ldh Release

The role of A1adenosine receptors (A1AR) in ischemic preconditioning was investigated in isolated crystalloid-perfused wild-type and transgenic mouse hearts with increased A1AR. The effect of preconditioning on postischemic myocardial function, lactate dehydrogenase (LDH) release, and infarct size was examined. Functional recovery was greater in transgenic versus wild-type hearts (44.8 ± 3.4% baseline vs. 25.6 ± 1.7%). Preconditioning improved functional recovery in wild-type hearts from 25.6 ± 1.7% to 37.4 ± 2.2% but did not change recovery in transgenic hearts (44.8 ± 3.4% vs. 44.5 ± 3.9%). In isovolumically contracting hearts, pretreatment with selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine attenuated the improved functional recovery in both wild-type preconditioned (74.2 ± 7.3% baseline rate of pressure development over time untreated vs. 29.7 ± 7.3% treated) and transgenic hearts (84.1 ± 12.8% untreated vs. 42.1 ± 6.8% treated). Preconditioning wild-type hearts reduced LDH release (from 7,012 ± 1,451 to 1,691 ± 1,256 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 32.3 ± 11.5%). Preconditioning did not affect LDH release or infarct size in hearts overexpressing A1AR. Compared with wild-type hearts, A1AR overexpression markedly reduced LDH release (from 7,012 ± 1,451 to 917 ± 1,123 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 6.5 ± 2.1%). These data demonstrate that murine preconditioning involves endogenous activation of A1AR. The beneficial effects of preconditioning and A1AR overexpression are not additive. Taken with the observation that A1AR blockade equally eliminates the functional protection resulting from both preconditioning and transgenic A1AR overexpression, we conclude that the two interventions affect cardioprotection via common mechanisms or pathways.

scholarly journals Cardiologic evaluation of patients undergoing chemoterapy

2015 ◽  
Vol 82 (2) ◽  
Author(s):  
Barbara Bordoni ◽  
Stefano Urbinati ◽  
Alicia Tosoni ◽  
Graziana Labanti ◽  
Alba Brandes
Keyword(s):  
Ventricular Dysfunction ◽  
Troponin I ◽  
Coronary Spasm ◽  
Left Ventricular ◽  
Cardiac Damage ◽  
Common Risk Factors ◽  
Selection For ◽  
Chemotherapy Cardiotoxicity

Life expectancy in patients affected by cancer has recently increased because of early diagnosis and actual therapies. In recent years, Oncology and Cardiology developed a tight relationship because of common risk factors (i.e. obesity, smoking, alcool intake, etc…), and for preventing the prothrombotic status due to cancer and the potential cardiotoxicity of chemotherapy. Cardiotoxicity incidence is reported from 1% up to 70% in retrospective analyses of drug protocols, mainly representing by left ventricular dysfunction (both reversible or irreversible), but also by arrhythmias, hypertension, atrioventricular block, coronary spasm, and arterial or venous thromboembolism. The early detection of the chemoterapy induced cardiotoxicity is now mandatory and can be obtained through a proper patients selection for different treatments and a strict monitoring during the follow-up period. The role of biomarkers of early cardiac damage, mainly, troponin I and brain natriuretic peptide-BNP, has been recently challenged, and algorithms are currently available. In the present paper, we propose how to perform a cardiological evaluation of patients undergoing chemoterapy tailored by the known adverse effects of the drugs.

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