Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis

2008 ◽  
Vol 294 (6) ◽  
pp. H2547-H2557 ◽  
Author(s):  
Qin-hui Tuo ◽  
Heng Zeng ◽  
Amanda Stinnett ◽  
Heidi Yu ◽  
Judy L. Aschner ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Critical Role ◽  
Myocardial Infarct Size ◽  
Vascular Integrity ◽  
Impaired Angiogenesis

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are the two ligands of the Tie-2 receptor, a receptor tyrosine kinase that is expressed on the endothelium. A balanced angiopoietin/Tie-2 system is critical for the maintenance of vascular integrity. We investigated the potential role of a disrupted angiopoietin/Tie-2 system on hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Using streptozotocin (STZ) mice subjected to myocardial ischemia, we examined the effects of shifting the Ang-2-to-Ang-1 ratio on myocardial infarction size, apoptosis, bone marrow (BM) cell-endothelial progenitor cell (EPC) differentiation, and angiogenesis. In control mice, myocardial ischemia increased expression of both Ang-2 and Tie-2. In STZ mice, Ang-2 expression was elevated, whereas Tie-2 expression was reduced, and neither was significantly altered by ischemia. Myocardial infarct size and apoptosis were increased in STZ compared with control mice. Using in vivo administration of an adenovirus containing Ang-1 or Ang-2, we found that shifting the Ang-2-to-Ang-1 ratio to favor Ang-1 reduced myocardial apoptosis and infarct size in STZ mice, while shifting the Ang-2-to-Ang-1 ratio to favor Ang-2 resulted in a significant increase in myocardial infarct size and apoptosis in control mice. Myocardial ischemia-stimulated BM cell-EPC differentiation was inhibited and myocardial angiogenesis was reduced in STZ mice. Systemic administration of Ad-Ang-1 restored BM cell-EPC differentiation and increased myocardial VEGF expression and angiogenesis in STZ mice. Our data demonstrate that disturbed angiopoietin/Tie-2 signaling contributes to the hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Restoration of the Ang-2-to-Ang-1 ratio may be a novel therapeutic strategy for the treatment of diabetic myocardial ischemic diseases.

Abstract 2894: Essential Role of ERK 1/2 in Sildenafil-Induced Early and Delayed Cardioprotection in Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Anindita das ◽  
Lei Xi ◽  
Fadi N Salloum ◽  
Yuan J Rao ◽  
Rakesh C Kukreja
Keyword(s):  
South Carolina ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Heart Association ◽  
Myocardial Infarct Size ◽  
Western Blots ◽  
Delayed Cardioprotection

Background: Sildenafil (SIL), a potent inhibitor of phosphodiesterase-5 induces powerful protection against myocardial ischemia-reperfusion (I-R) injury through activation of protein kinase G (PKG). However, the downstream targets of PKG in SIL-induced cardioprotection remain unclear. We hypothesized that PKG-dependent activation of survival kinase, ERK may play a critical role in SIL-induced cardioprotection in mice. Methods & Results: Ventricular myocytes were isolated from adult male ICR mice and exposed to 40 min of simulated ischemia (SI) with/without 1 hr pre-incubation of SIL (1 μM). Myocyte necrosis and apoptosis were determined after 1 hr or 18 hrs of reoxygenation (RO) using trypan blue or TUNEL assay, respectively. Pretreatment with SIL protected cardiomyocytes after SI-RO (necrosis 18.5±0.5% and apoptosis 6.6±0.7%; n=4, p<0.001) as compared with controls (necrosis 42.1±1.8% and apoptosis 23.3±0.9%). Co-incubation of PD98059 (20 μM), a selective ERK1/2 inhibitor blocked both anti-necrotic and anti-apoptotic protection in cardiomyocytes. Furthermore, intra-coronary infusion of SIL (1 μM) in Langendorff isolated mouse hearts 10 min prior to zero-flow global I (20 min) and R (30 min) significantly reduced myocardial infarct size (from 29.4±2.4% to 16.0±3.0%; p<0.05, n=6). Co-treatment of PD98059 abrogated SIL-induced protection (33.0±5.9; n=4). To evaluate the role of ERK1/2 in delayed cardioprotection, mice were treated with saline or SIL (0.7 mg/kg i.p.) 24 hours before global I-R in Langendorff mode. PD98059 (1 mg/kg) was administered (i.p.) 30 min before the treatment of SIL. Infarct size was reduced from 27.6±3.3% in saline-treated controls to 6.9±1.2% in SIL-treated mice (P<0.05, n=6). The delayed protective effect of SIL was also abolished by PD98059 (22.5±2.3%). Western Blots revealed that SIL significantly increased phosphorylation of ERK1/2 which was blocked by PKG inhibitor, KT5823 in the heart and adult myocytes. Selective knockdown of PKG in cardiomyocytes with short hairpin RNA of PKG also blocked the phosphorylation of ERK1/2. Conclusion: SIL-induced cardioprotection involves the activation and phosphorylation of ERK which appear to be intimately linked with a PKG-dependent survival pathway. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).

Abstract 145: Apelin Reduces Myocardial Infarction Size and Promotes Angiogenesis by Increasing SDF-1/CXCR4 and AKT/eNOS/VEGF Pathways

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Lanfang Li ◽  
Heng Zeng ◽  
Jian-xiong Chen
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Molecular Mechanisms ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Heart Weight ◽  
Tunel Staining ◽  
Myocardial Infarct Size

Background: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and is emerging as a key player in the regulation of angiogenesis as well as ischemia/reperfusion injury. So far, little is known about the functional role of apelin in myocardial ischemia. We investigated the potential intracellular molecular mechanisms and protective role of apelin during myocardial ischemic injury. Methods and Results: Myocardial ischemia was achieved by ligation of the left anterior descending coronary artery (LAD) for 24 hours and 14 days. Myocardial apoptosis was detected by TUNEL staining. Akt, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), SDF-1 and CXCR4 expression were measured by western blot. The CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells were determined by immunostaining. Myocardial capillary and arteriole densities were analyzed in the border zone of infarcted myocardium at 14 d of ischemia. Treatment of C57BL/6J mice with apelin-13 (1 mg/Kg.d) by i.p. injection for 3 days before surgery results in significant decreases in TUNEL positive cells and myocardial infarct size at 24 hours of ischemia. Treatment with apelin increases the phosphorylation of AKT and eNOS and upregulates VEGF expression in the ischemic heart. Furthermore, treatment with apelin leads to the expression of SDF-1 and CXCR4 and increases in the number of CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells in ischemic hearts. Treatment with apelin also significantly increases myocardial capillary densities and arteriole formation together with a significant decrease in the ratio of heart weight to body weight at 14 days of ischemia. This is accompanied by a significant improvement of cardiac function after 14 days of ischemia. Conclusions: Our data demonstrate that apelin contributes to the protection of myocardial infarction and angiogenesis by the mechanisms involving in upregulation of SDF-1/CXCR4 and AKT/eNOS/VEGF pathways.

Morphine Enhances Pharmacological Preconditioning by Isoflurane

2003 ◽  
Vol 98 (3) ◽  
pp. 705-711 ◽  
Author(s):  
Lynda M. Ludwig ◽  
Hemal H. Patel ◽  
Garrett J. Gross ◽  
Judy R. Kersten ◽  
Paul S. Pagel ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Potassium Channels ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Opioid Receptors ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk

Background Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors. Methods Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane. Results Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane. Conclusions Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.

Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury

1998 ◽  
Vol 275 (5) ◽  
pp. H1865-H1872 ◽  
Author(s):  
Anthony J. Palazzo ◽  
Steven P. Jones ◽  
Donald C. Anderson ◽  
D. Neil Granger ◽  
David J. Lefer
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia Reperfusion

We investigated in vivo coronary P-selectin expression and its pathophysiological consequences in a murine model of myocardial ischemia-reperfusion (MI/R) using wild-type and P-selectin deficient (−/−) mice. Coronary P-selectin expression [μg monoclonal antibody (MAb)/g tissue] was measured using a radiolabeled MAb method after 30 min of myocardial ischemia and 20 min of reperfusion. P-selectin expression in wild-type mice was significantly ( P< 0.01) elevated in the ischemic zone (0.070 ± 0.010) compared with the nonischemic zone (0.037 ± 0.008). Myocardial P-selectin expression was nearly undetectable in P-selectin −/− mice after MI/R. Furthermore, myocardial infarct size (% of area at risk) after 30 min of myocardial ischemia and 120 min of reperfusion was 42.5 ± 4.4 in wild-type mice and 24.4 ± 4.0 in P-selectin −/− mice ( P < 0.05). In additional experiments of prolonged myocardial ischemia (60 min) and reperfusion (120 min), myocardial infarct size was similar in P-selectin −/− mice and wild-type mice. Our results clearly demonstrate the involvement of coronary P-selectin in the development of myocardial infarction after MI/R.

scholarly journals Phosphatidylserine Supplementation as a Novel Strategy for Reducing Myocardial Infarct Size and Preventing Adverse Left Ventricular Remodeling

2021 ◽  
Vol 22 (9) ◽  
pp. 4401
Author(s):  
David Schumacher ◽  
Adelina Curaj ◽  
Mareike Staudt ◽  
Franziska Cordes ◽  
Andreea R. Dumitraşcu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Novel Strategy

Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil’s activation, such as Interleukin 1 beta (IL-1β) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.

scholarly journals Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

2018 ◽  
Vol 45 (3) ◽  
pp. 883-898 ◽  
Author(s):  
Yinping Du ◽  
Ping Liu ◽  
Tongda Xu ◽  
Defeng Pan ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background/Aims: The myocardial sarcoplasmic reticulum calcium ATPase (SERCA2a) is a pivotal pump responsible for calcium cycling in cardiomyocytes. The present study investigated the effect of luteolin (Lut) on restoring SERCA2a protein level and stability reduced by myocardial ischemia/reperfusion (I/R) injury. We verified a hypothesis that Lut protected against myocardial I/R injury by regulating SERCA2a SUMOylation. Methods: The hemodynamic data, myocardial infarct size of intact hearts, apoptotic analysis, mitochondrial membrane potential (ΔΨm), the level of SERCA2a SUMOylation, and the activity and expression of SERCA2a were examined in vivo and in vitro to clarify the cardioprotective effects of Lut after SUMO1 was knocked down or over-expressed. The putative SUMO conjugation sites in mouse SERCA2a were investigated as the possible regulatory mechanism of Lut. Results: Initially, we found that Lut reversed the SUMOylation and stability of SERCA2a as well as the expression of SUMO1, which were reduced by I/R injury in vitro. Furthermore, Lut increased the expression and activity of SERCA2a partly through SUMO1, thus improving ΔΨm and reducing apoptotic cells in vitro and promoting the recovery of heart function and reducing infarct size in vivo. We also demonstrated that SUMO acceptor sites in mouse SERCA2a involving lysine 585, 480 and 571. Among the three acceptor sites, Lut enhanced SERCA2a stability via lysine 585. Conclusions: Our results suggest that Lut regulates SERCA2a through SUMOylation at lysine 585 to attenuate myocardial I/R injury.

Abstract P290: RhoA Protects Against Myocardial Ischemia/Reperfusion Injury

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Sunny Y Xiang ◽  
Shigeki Miyamoto ◽  
Davy Vanhoutte ◽  
Jeffery D Molkentin ◽  
Gerald W Dorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Contractile Function ◽  
Ex Vivo ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Small Gtpase ◽  
Myocardial Infarct Size ◽  
Rhoa Signaling

The small GTPase RhoA has established effects on cytoskeletal dynamics and gene expression but its role in regulating cardiac physiology and disease remains elusive. To characterize the in vivo role of RhoA signaling in cardiomyocytes, we generated conditional cardiac-specific RhoA transgenic mice (CA-RhoA) with 2–5 fold increases in RhoA activation in the adult heart. CA-RhoA mice show no overt cardiomyopathy but when challenged by in vivo or ex vivo I/R, these mice exhibit strikingly increased tolerance to injury. Compared to control mice, myocardial infarct size in CA-RhoA mice is reduced by 60–70% (20% vs. 50%, ex vivo; 10% vs. 37%, in vivo) and recovery of contractile function is significantly improved. Protein kinase D (PKD) is robustly activated in CA-RhoA hearts and inhibiting PKD reverses the cardioprotection afforded by RhoA. Both RhoA and PKD are also activated during I/R and blocking PKD augments I/R injury in WT mouse hearts. To further confirm that RhoA and PKD play a protective role during I/R, cardiac-specific RhoA knockout mice generated in the Molkentin laboratory were tested and demonstrated to show decreased tolerance to I/R injury, manifests as increased infarct size (42% vs. 23%) and lactate dehydrogenase release relative to control mice. This was accompanied by attenuated PKD activation during I/R. Taken together, our data indicates that RhoA signaling in adult cardiomyocytes promotes survival and reveals an unexpected role of PKD as a downstream mediator of RhoA and on cardioprotection against I/R.

Acute hyperglycemia abolishes ischemic preconditioning in vivo

1998 ◽  
Vol 275 (2) ◽  
pp. H721-H725 ◽  
Author(s):  
Judy R. Kersten ◽  
Todd J. Schmeling ◽  
Karl G. Orth ◽  
Paul S. Pagel ◽  
David C. Warltier
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Plasma Glucose ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Acute Hyperglycemia

Ischemic preconditioning provides a powerful means to reduce myocardial infarct size in vivo and has been proposed to limit the extent of myocardial infarction in patients. In contrast, hyperglycemia correlates with increases in mortality after acute myocardial infarction. Thus we hypothesized that acute hyperglycemia alters the protection afforded by ischemic preconditioning, and this hypothesis was tested in acutely instrumented dogs subjected to a prolonged (60 min) coronary artery occlusion and 3 h of reperfusion. Ischemic preconditioning was elicited by four 5-min occlusion-reperfusion periods in the presence or absence of an intravenous infusion of 15% dextrose in water to produce acute hyperglycemia (plasma glucose concentration of 300 mg/dl). The dose-dependent effects of hyperglycemia on myocardial infarct size independent of preconditioning stimuli were further evaluated in dogs subjected to increases in plasma glucose concentrations to either 300 or 600 mg/dl. Infarct size (triphenyltetrazolium staining) was 24 ± 2% of the area at risk in control dogs and was significantly ( P < 0.05) decreased by ischemic preconditioning (8 ± 1%). Modest degrees of hyperglycemia (300 mg/dl) had no effect on infarct size (34 ± 4%) but abolished the protective effect of ischemic preconditioning (30 ± 5%). In contrast, profound hyperglycemia (600 mg/dl) increased infarct size (44 ± 6%). Hemodynamics and coronary collateral blood flow (radioactive microspheres) were similar between groups. Thus acute hyperglycemia adversely modulates myocardial injury in response to ischemia in vivo.

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