Anti-Apoptotic Effect of Magnolol in Myocardial Ischemia and Reperfusion Injury Requires Extracellular Signal-Regulated Kinase1/2 Pathways in Rat In Vivo

2008 ◽  
Vol 233 (10) ◽  
pp. 1280-1288 ◽  
Author(s):  
Yong Chun Jin ◽  
Kil Jung Kim ◽  
Young Min Kim ◽  
Yu Mi Ha ◽  
Hye Jung Kim ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Function Analysis ◽  
Heart Function ◽  
Myocardial Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion

Magnolol, an active component extracted from Magnolia officinalis, has been reported to have protective effect on ischemia and reperfusion (I/R)-induced injury in experimental animals. The aim of the present investigation was to further evaluate the mechanism(s) by which magnolol reduces I/R-induced myocardial injury in rats in vivo. Under anesthesia, left anterior descending (LAD) coronary artery was occluded for 30 min followed by reperfusion for 24 h (for infarct size and cardiac function analysis). In some experiments, reperfusion was limited to 1 h or 6 h for analysis of biochemical and molecular events. Magnolol and DMSO solution (vehicle) were injected intra-peritoneally 1 h prior to I/R insult. The infarct size was measured by TTC technique and heart function was monitored by Millar Catheter. Apoptosis related events such as p-ERK, p-Bad, Bcl-xl and cytochrome c expression were evaluated by Western blot analysis and myocardial caspase-3 activity was also measured. Magnolol (10 mg/kg) reduced infarct size by 50% ( P < 0.01 versus vehicle), and also improved I/R-induced myocardial dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in magnolol-treated rats. Magnolol increased the expression of phosphor ERK and Bad which resulted in inhibition of myocardial apoptosis as evidenced by TUNEL analysis and DNA laddering experiments. Application of PD 98059, a selective MEK1/2 inhibitor, strongly antagonized the effect of magnolol. Taken together, we concluded that magnolol inhibits apoptosis through enhancing the activation of ERK1/2 and modulation of the Bcl-xl proteins which brings about reduction of infarct size and improvement of cardiac function in I/R-induced injury.

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

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.

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.

Cardiac function in spontaneously hypertensive diabetic rats

1986 ◽  
Vol 251 (3) ◽  
pp. H571-H580 ◽  
Author(s):  
B. Rodrigues ◽  
J. H. McNeill
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Myocardial Dysfunction ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Developed Pressure ◽  
Working Heart ◽  
Diabetes Induction

The isolated perfused working heart was used to study hypertensive diabetes-induced alterations in cardiac function at 6 and 12 wk after diabetes was induced. At 6 wk after diabetes induction, cardiac performance was depressed in the diabetic animals. However, there was no difference in cardiac function between normotensive Wistar and spontaneously hypertensive (SHR) diabetic rats. Wistar-Kyoto (WKY) rats were also included as normotensive controls in our 12-wk study. Hearts from 12-wk SHR and Wistar diabetic animals exhibited a depressed left ventricular developed pressure and positive and negative dP/dt when compared with control animals. However, this depression was not seen in the WKY diabetic animals. In addition, quantitation of various parameters of heart function revealed highly significant differences between SHR diabetic animals and all other groups associated with an increased mortality. Serum lipids were elevated in SHR and Wistar and were unaffected in WKY diabetic rats. Furthermore, thyroid hormone levels were not depressed in WKY diabetic rats as seen in the other two diabetic groups. This normal lipid metabolism and thyroid status could, in part, explain the lack of cardiac dysfunction in these animals. The data provide further evidence that the combination of hypertension and diabetes mellitus produces greater myocardial dysfunction than with either disease alone and is associated with a significant mortality.

scholarly journals Decreased cardiac SERCA2 expression, SR Ca uptake, and contractile function in hypothyroidism are attenuated in SERCA2 overexpressing transgenic rats

2011 ◽  
Vol 300 (3) ◽  
pp. H943-H950 ◽  
Author(s):  
Roland Vetter ◽  
Uwe Rehfeld ◽  
Christoph Reissfelder ◽  
Henry Fechner ◽  
Enn Seppet ◽  
...  
Keyword(s):  
Contractile Function ◽  
Heart Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Loss Of Function ◽  
Transgenic Rats ◽  
Mrna Ratio ◽  
And Function

The sarco/endoplasmic reticulum (SR) Ca2+-ATPase SERCA2a has a key role in controlling cardiac contraction and relaxation. In hypothyroidism, decreased expression of the thyroid hormone (TH)-responsive SERCA2 gene contributes to slowed SR Ca2+ reuptake and relaxation. We investigated whether cardiac expression of a TH-insensitive SERCA2a cDNA minigene can rescue SR Ca2+ handling and contractile function in female SERCA2a-transgenic rats (TG) with experimental hypothyroidism. Wild-type rats (WT) and TG were rendered hypothyroid by 6- N-propyl-2-thiouracil treatment for 6 wk; control rats received no treatment. In vivo measured left ventricular (LV) hemodynamic parameters were compared with SERCA2a expression and function in LV tissue. Hypothyroidism decreased LV peak systolic pressure, dP/d tmax, and dP/d tmin in both WT and TG. However, loss of function was less in TG. Thus slowed relaxation in hypothyroidism was found to be 1.5-fold faster in TG compared with WT ( P < 0.05). In parallel, a 1.4-fold higher Vmax value of homogenate SR Ca2+ uptake was observed in hypothyroid TG ( P < 0.05 vs. hypothyroid WT), and the hypothyroidism-caused decline of LV SERCA2a mRNA expression in TG by −24% was markedly less than the decrease of −49% in WT ( P < 0.05). A linear relationship was observed between the SERCA2a/PLB mRNA ratio values and the Vmax values of SR Ca2+ uptake when the respective data of all experimental groups were plotted together ( r = 0.90). The data show that expression of the TH-insensitive SERCA2a minigene compensates for loss of expressional activity of the TH-responsive native SERCA2a gene in the female hypothyroid rat heart. However, SR Ca2+ uptake and in vivo heart function were only partially rescued.

Impact of exercise training on ventricular properties in a canine model of congestive heart failure

1997 ◽  
Vol 272 (3) ◽  
pp. H1382-H1390 ◽  
Author(s):  
K. Todaka ◽  
J. Wang ◽  
G. H. Yi ◽  
M. Knecht ◽  
R. Stennett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Heart Function ◽  
Systolic Pressure ◽  
Cardiac Pacing ◽  
Left Ventricular ◽  
Lv Function ◽  
Myocardial Stiffness

Exercise training improves functional class in patients with chronic heart failure (CHF) via effects on the periphery with no previously documented effect on intrinsic left ventricular (LV) properties. However, because methods used to evaluate in vivo LV function are limited, it is possible that some effects of exercise training on the failing heart have thus far eluded detection. Twelve dogs were instrumented for cardiac pacing and hemodynamic recordings. Hearts were paced rapidly for 4 wk. Six of the dogs received daily treadmill exercise (CHF(EX), 4.4 km/h, 2 h/day) concurrent with rapid pacing, while the other dogs remained sedentary (CHFs). Hemodynamic measurements taken in vivo at the end of 4 wk revealed relative preservation of maximum rate of pressure rise (2,540 +/- 440 vs. 1,720 +/- 300 mmHg/s, P < 0.05) and LV end-diastolic pressure (9 +/- 5 vs. 19 +/- 4 mmHg, P < 0.05) in CHF(EX) compared with CHFs. The hearts were then isolated and cross perfused for in vitro measurement of isovolumic pressure-volume relations; these results were compared with those of six normal dogs (N). Systolic function was similarly depressed in both groups of pacing animals [end-systolic elastance (Ees) values of 1.66 +/- 0.47 in CHFs, 1.77 +/- 0.38 in CHF(EX), and 3.05 +/- 0.81 mmHg/ml in N, with no changes in volume axis interceptors of the end-systolic pressure-volume relationship]. The diastolic myocardial stiffness constant, k, was elevated in CHFs and was normalized by exercise training (32 +/- 3 in CHFs, 21 +/- 3 in CHF(EX), 20 +/- 4 in N). Thus daily exercise training preserved in vivo hemodynamics during 4 wk of rapid cardiac pacing and was accompanied by a significant change in diastolic myocardial stiffness in vitro. These findings suggest that changes in heart function may contribute to the overall beneficial hemodynamic effects of exercise training in CHF by a significant effect on diastolic properties.

scholarly journals Diverse Effects of L-arginine on Cardiac Function of Rats Subjected to Myocardial Ischemia and Reperfusion in vivo

2007 ◽  
Vol 39 (3) ◽  
pp. 201-207 ◽  
Author(s):  
Xiaoliang WANG ◽  
Feng LIANG ◽  
Xiangying JIAO ◽  
Lei LIU ◽  
Xiaojie BAI ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion

Abstract 20587: Myocyte-Specific Over-Expression of Hdac4 Promotes Myocardial Ischemia and Reperfusion Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ling Zhang ◽  
Jian Feng Du ◽  
Yu Zhao ◽  
Ting C Zhao
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Left Ventricular ◽  
Heart Weight ◽  
Ischemia And Reperfusion ◽  
Wild Type ◽  
Ischemia And Reperfusion Injury ◽  
Myocardial Ischemia And Reperfusion ◽  
Over Expression

Background: Histone deacetylases (HDACs) have been recently demonstrated to play a critical role in modulating myocardial protection and cardiomyocyte survival. However, the specific HDAC in mediating myocardial ischemia/reperfusion injury is currently unknown. Objective: The goal of this study is sought to define whether cardiac specific over-expression of HDAC4 would exacerbate myocardial ischemia and reperfusion injury. Methods: We created myocyte-specific HDAC4 transgenic mice, in which cDNA encoding HDAC4 was cloned into an expression vector encoding alpha-myosine heavy chain (the α-MHC promoter). Langendorff isovolumetrically perfused hearts from wild type (WT) control (n=5) and α-MHC-HDAC4 mice (n=5) were subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Infarct size was measured by triphenyl tetrazolium chloride staining. HDAC4 protein and activity in myocardium were determined. Results: The HDAC4 protein levels in the hearts of α-MHC-HDAC4 mice were significantly higher than those of control wild type. HDAC activity was elevated in MHC-HDAC4 mice as compared with wild type mice. In adult mice, there was no significant difference in the heart weight-body weight ratio between α-MHC-HDAC and wild-type mice. As compared to wild type mice, myocyte-specific over-expression of HDAC4 resulted in an elevation of left ventricular end-diastolic pressure (LVEDP) and reduction in the recovery of rate and pressure products (RPP) at the end of reperfusion. Furthermore, over-expression of HDAC4 increased myocardial infarct size as compared to wild type mice. Conclusions: These findings indicate that specific over-expression of HDAC4 exacerbates myocardial ischemia and reperfusion injury.

Abstract 4031: Nitric Oxide Synthase 3 Deficiency Worsens Myocardial Dysfunction and Survival in Murine Polymicrobial Sepsis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masahiko Bougaki ◽  
Robert J Searles ◽  
Jia D Yu ◽  
Gian Paolo Volpate ◽  
Fumito Ichinose
Keyword(s):  
Cardiac Function ◽  
Production Rate ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Polymicrobial Sepsis ◽  
Atp Production ◽  
Cardiac Inflammation ◽  
Myocardial Mitochondria ◽  
Hemodynamic Study

Background: Myocardial dysfunction during sepsis contributes to the high mortality of patients with septic shock. The role of NOS3 on cardiac function during sepsis remains incompletely understood. Here, we examined impact of NOS3 deficiency on myocardial function and survival during peritonitis-induced polymicrobial sepsis. Methods: Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3 deficient (KO) mice. Cardiac function was examined both in vivo hemodynamic study and in isolated left ventricular cardiomyocytes, where sarcomere length (SL) and intracellular calcium transients ([Ca 2+ ] i ) were measured by video-edge detection and Fura-2 fluorescence, respectively. Mitochondrial function was assessed by measuring the ATP production rate in isolated mitochondria from left ventricle. Results: Mortality at 24 hours after CASP was higher in KO (15/15, 100%) than in WT (13/20, 65%, P<0.05 vs KO). In vivo hemodynamic study 22 hours after CASP revealed both systolic and diastolic cardiac functions were impaired to a greater extent in KO than in WT. In isolated cardiomyocytes, CASP induced-reduction in percent SL shortening and the peak amplitude of [Ca 2+ ] i was more marked in NOS3KO than in WT. The time constants for SL relengthening and diastolic [Ca 2+ ] i decay were prolonged to a greater extent in KO than in WT after CASP. Cardiac inflammation estimated by expression levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) was more pronounced in KO than in WT. CASP-induced reduction in ATP production rate of myocardial mitochondria was more marked in KO than in WT, which was associated with reduction in mitochondrial complex I activity. Conclusions: These results suggest that NOS3 deficiency aggravates myocardial dysfunction through mitochondrial dysfunction and decreases survival after peritonitis-induced polymicrobial sepsis in mice. Table Hemodynamic and myocyte study 22 hours after CASP or sham

Hyperbaric Oxygen Preconditioning Alleviates Myocardial Ischemic Injury in Rats

2008 ◽  
Vol 233 (11) ◽  
pp. 1448-1453 ◽  
Author(s):  
Cuihong Han ◽  
Li Lin ◽  
Weidong Zhang ◽  
Li Zhang ◽  
Shijun Lv ◽  
...  
Keyword(s):  
Infarct Size ◽  
Hyperbaric Oxygen ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Capillary Density ◽  
Left Ventricular ◽  
Ischemic Myocardium ◽  
Sham Surgery ◽  
Vegf Protein

It has been shown that after ischemia-reperfusion, application of hyperbaric oxygen (HBO) reduces cardiac injury. In this study we tested the hypothesis that HBO preconditioning reduces injury to the ischemic myocardium. One hundred and eight adult male Sprague-Dawley rats (250–280 g) were randomly divided into four groups: normoxia + sham surgery (CS), normoxia + permanent occlusion of the left anterior descending (LAD) coronary artery (CMI), HBO preconditioning + sham surgery (HS), and HBO preconditioning + permanent LAD occlusion (HMI). Rats receiving HBO preconditioning were intermittently exposed to 100% O2 at 2.5 atmosphere absolute (ATA) for 60 min, twice daily for 2 days followed by 12 hrs of recovery in room air prior to the myocardial ischemic insult induced by LAD ligation. Rats in the normoxia group were time-matched with the HBO group and maintained under normoxic conditions prior to LAD occlusion. At 3 and 7 days after LAD occlusion, heart function parameters were measured by inserting a catheter into the left ventricle, infarct size was calculated using the method of TTC staining, myocardial capillary density was determined by immunohistochemical staining with a monoclonal anti-CD31/PECAM-1 antibody, and VEGF protein level was determined by Western blot analysis. At 3 days after LAD ligation, the infarct size of the HMI group was significantly smaller than that of the CMI group (26 ± 2.5% vs. 38 ± 3%, P < 0.05). The heart function parameters including left ventricular systolic pressure (LVSP), +dP/dtmax and −dP/dtmax were significantly improved in the HMI group compared to the CMI group at 3 and 7 days after LAD occlusion. Capillary density and VEGF protein levels were significantly increased in the ischemic myocardium pre-exposed to HBO. We conclude that HBO preconditioning alleviates myocardial ischemia in rat model.

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