Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

2008 ◽  
Vol 295 (6) ◽  
pp. H2436-H2446 ◽  
Author(s):  
Yumei Ye ◽  
Yu Lin ◽  
Saraswathy Manickavasagam ◽  
J. Regino Perez-Polo ◽  
Brian C. Tieu ◽  
...  
Keyword(s):  
Protective Effect ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Peroxisome Proliferator ◽  
Myocardial Infarct Size ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inos Knockout Mice

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-γ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1α levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS−/− and iNOS−/− mice. Male C57BL/6 wild-type (WT), eNOS−/−, and iNOS−/− mice received 10 mg·kg−1·day−1 Pio (Pio+) or water alone (Pio−) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 ± 1.4% vs. 39.0 ± 1.1%; P < 0.001), as well as in the eNOS−/− (32.0 ± 1.6% vs. 44.2 ± 1.9%; P < 0.001) and iNOS−/− (18.0 ± 1.2% vs. 45.5 ± 2.3%; P < 0.001) mice. The protective effect of Pio in eNOS−/− mice was smaller than in the WT ( P < 0.001) and iNOS−/− ( P < 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS−/− mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS−/− and iNOS−/−, mice. Pio increased the myocardial 6-keto-PGF1α levels and cPLA2 and COX2 activity in the WT, eNOS−/−, and iNOS−/− mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.

Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2

2005 ◽  
Vol 289 (4) ◽  
pp. H1618-H1626 ◽  
Author(s):  
Chad E. Darling ◽  
Rong Jiang ◽  
Michelle Maynard ◽  
Peter Whittaker ◽  
Jakob Vinten-Johansen ◽  
...  
Keyword(s):  
Infarct Size ◽  
Kinase Inhibitor ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Pi3 Kinase ◽  
Myocardial Infarct Size ◽  
Downstream Target

Emerging evidence suggests that restoration of blood flow in a stuttering manner may limit lethal myocardial ischemia-reperfusion injury. However, the mechanisms contributing to this phenomenon, termed postconditioning (post-C), remain poorly defined. Our aim was to test the hypothesis that activation of classic “survival kinases,” phosphatidylinositol 3-kinase (PI3-kinase) and/or extracellular signal-regulated kinase (ERK)1/2, may play a role in post-C-induced cardioprotection. In protocol 1, isolated buffer-perfused rabbit hearts underwent 30 min of sustained coronary artery occlusion and were randomized to receive abrupt reperfusion (controls) or four cycles of 30 s of reperfusion and 30 s of reocclusion before full restoration of flow (post-C). Protocol 2 was identical except control and postconditioned hearts received the PI3-kinase inhibitor LY-294002 ( protocol 2A) or the ERK1/2 antagonist PD-98059 ( protocol 2B) throughout the first 25 min of reperfusion, whereas in protocol 3, myocardial samples were obtained during the early minutes of reflow from additional control, postconditioned, and nonischemic sham hearts for the assessment, by standard immunoblotting, of phospho-Akt (downstream target of PI3-kinase) and phospho-ERK. Protocols 1 and 2 corroborated that infarct size (delineated by tetrazolium staining and expressed as a percent of risk region) was reduced in postconditioned hearts vs. control hearts and also revealed that post-C-induced cardioprotection was maintained despite LY-294002 treatment but was abrogated by PD-98059. These pharmacological data were supported by protocol 3, which showed increased immunoreactivity of phospho-ERK but not phospho-Akt with post-C. Thus our results implicate the involvement of ERK1/2 rather than PI3-kinase/Akt in the reduction of infarct size achieved with post-C.

Cytoprotective effects ofN,N,N-trimethylsphingosine during ischemia- reperfusion injury are lost in the setting of obesity and diabetes

2007 ◽  
Vol 293 (4) ◽  
pp. H2462-H2471 ◽  
Author(s):  
Susheel Gundewar ◽  
John W. Calvert ◽  
John W. Elrod ◽  
David J. Lefer
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Biological Effects ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Wild Type ◽  
Obesity And Diabetes

N, N, N-Trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analog, has been shown to modulate protein kinase C (PKC) activity and exert a number of important biological effects, including inhibition of tumor cell growth and metastasis, inhibition of leukocyte migration and respiratory burst, and inhibition of platelet aggregation. We hypothesized that TMS would be cytoprotective in clinically relevant in vivo murine models of myocardial and hepatic ischemia-reperfusion (I/R) injury. Wild-type, obese ( ob/ ob), and diabetic ( db/ db) mice were subjected to 30 min of left coronary artery occlusion followed by 24 h of reperfusion in the myocardial I/R model. In additional studies, mice were subjected to 45 min of hepatic artery occlusion followed by 5 h of reperfusion. TMS was administered intravenously at the onset of ischemia. Myocardial infarct size, cardiac function, and serum liver enzymes were measured to assess the extent of tissue injury. TMS attenuated myocardial infarct size by 66% in the wild type and by 36% in the ob/ ob mice. Furthermore, TMS reduced serum alanine transaminase levels by 43% in wild-type mice. These benefits did not extend to the ob/ ob mice following hepatic I/R or to the db/ db mice following both myocardial and hepatic I/R. A likely mechanism is the failure of TMS to inhibit PKC-δ translocation in the diseased heart. These data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals.

scholarly journals Protective Effect of Peroxisome Proliferator-Activated ReceptorαActivation against Cardiac Ischemia-Reperfusion Injury Is Related to Upregulation of Uncoupling Protein-3

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Jong Wook Song ◽  
Hyo Jung Kim ◽  
Hyelin Lee ◽  
Jae-woo Kim ◽  
Young-Lan Kwak
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Uncoupling Protein ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Myocardial Infarct Size ◽  
Ros Production ◽  
H9c2 Cells ◽  
Ucp3 Expression ◽  
Hypoxia Reoxygenation

Activation of peroxisome proliferator-activated receptorα(PPARα) confers cardioprotection, while its mechanism remains elusive. We investigated the protective effect of PPARαactivation against cardiac ischemia-reperfusion injury in terms of the expression of uncoupling protein (UCP). Myocardial infarct size and UCP expression were measured in rats treated with WY-14643 20 mg/kg, a PPARαligand, or vehicle. WY-14643 increased UCP3 expressionin vivo. Myocardial infarct size was decreased in the WY-14643 group (76 ± 8% versus 42 ± 12%,P<0.05). During reperfusion, the incidence of arrhythmia was higher in the control group compared with the WY-14643 group (9/10 versus 3/10,P<0.05). H9c2 cells were incubated for 24 h with WY-14643 or vehicle. WY-14643 increased UCP3 expression in H9c2 cells. WY-14643 decreased hypoxia-stimulated ROS production. Cells treated with WY-14643 were more resistant to hypoxia-reoxygenation than the untreated cells. Knocking-down UCP3 by siRNA prevented WY-14643 from attenuating the production of ROS. UCP3 siRNA abolished the effect of WY-14643 on cell viability against hypoxia-reoxygenation. In summary, administration of PPARαagonist WY-14643 mitigated the extent of myocardial infarction and incidence of reperfusion-induced arrhythmia. PPARαactivation conferred cytoprotective effect against hypoxia-reoxygenation. Associated mechanisms involved increased UCP3 expression and resultant attenuation of ROS production.

Abstract 3878: Glucagon-Like Peptide-1 Metabolite Protects the Myocardium Against Ischemia-Reperfusion Injury in Diabetes Mellitus

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Susheel Gundewar ◽  
John W Elrod ◽  
John W Calvert ◽  
Xuelaing Du ◽  
Diane Edelstein ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Diabetic Mice ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background: Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone with potent plasma glucose lowering actions that is rapidly degraded by the enzyme Dipeptidyl Peptidase-IV to GLP-1(9 –36) amide . GLP-1(9 –36) amide (GLP1dp) has previously been viewed to be biologically inactive. However, our laboratory has demonstrated that GLP1dp inhibits hyperglycemia-induced production of oxidant species and prevents the inactivation of both eNOS and prostacyclin synthase in cells and diabetic animals. We investigated the effects of GLP1dp in two in vivo diabetic murine models of myocardial ischemia-reperfusion (MI-R) injury. Methods: Diabetic (db/db and STZ-diabetic) mice were treated with 2.4 μg/day of GLP1dp via Alzet pump for 7 days and subjected to 45 min of left coronary artery occlusion and 2 hr of R. At 2 hr of R, hearts were excised and evaluated for infarct (INF) size. Results: Diabetic (db/db) and STZ-diabetic mice treated with GLP1dp exhibited a 37% and 33% reduction in myocardial infarct size following MI-R respectively. Additionally, GLP1dp significantly reduced oxidative stress in the myocardium of these mice. Both models of diabetic mice (db/db and STZ-diabetic) exhibited elevated baseline blood glucose (BG) values of 386 ± 25 and 435 ± 15 mg/dl respectively. After 7 days of GLP1dp therapy, db/db mice exhibited a 48% reduction in BG values. In contrast, no reduction in BG was observed in the STZ-diabetic mice. Conclusion : Administration of GLP1dp peptide confers cardioprotection in diabetic mice by attenuating the extent of oxidant-mediated injury following MI-R. The cardioprotective actions of GLP1dp appear to be independent of any effects on blood glucose.

scholarly journals Influence of ramiprilat and losartan on ischemia reperfusion injury in rat hearts

2011 ◽  
Vol 13 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Fatemeh Safari ◽  
Sohrab Hajizadeh ◽  
Shahnaz Shekarforoush ◽  
Gholamreza Bayat ◽  
Mohsen Foadoddini ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Saline Group ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Dependent Manner ◽  
Protective Effects

Hypothesis/introduction: Our aim was to investigate whether a non-hypotensive dose of ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo. Materials and methods: Three groups of rats were given 10 mg/kg per day of losartan for one (L-1W), four (L-4W) or 10 (L-10W) weeks. Another three groups were given 50 µg/kg per day of ramiprilat for one (R-1W), four (R-4W) or 10 (R-10W) weeks. The animals underwent 30 min of left anterior descending artery occlusion and subsequent reperfusion for 120 min. Results: Myocardial infarct size (IS) was reduced in R-1W (28.4 ± 6.3%, p < 0.001), R-4W (27.8 ± 7.4, p < 0.001), L-4W (31.8 ± 6%, p < 0.05) and L-10W (25.3 ± 5.7, p < 0.001) groups compared with a saline group (48.3 ± 7.8%). A significant reduction in the number of ventricular ectopic beats (VEBs) was noted in groups R-1W (209 ± 41, p < 0.01), R-4W (176 ± 39, p < 0.01), L-4W (215 ± 52, p < 0.05) and L-10W (191 ± 61, p < 0.01 vs. saline 329 ± 48). The incidence of irreversible ventricular fibrillation (VF) and mortality were decreased significantly only in L-10W group. There were no significant decreases in episodes of VT, the incidence of irreversible VF and mortality in all of the groups treated with ramiprilat. Conclusion: These data indicate that losartan and ramiprilat protect the heart against ischemia/reperfusion injury independently of their hemodynamic effects but in a time-dependent manner.

scholarly journals Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice

2008 ◽  
Vol 295 (4) ◽  
pp. H1580-H1586 ◽  
Author(s):  
Omar Bouhidel ◽  
Sandrine Pons ◽  
Richard Souktani ◽  
Roland Zini ◽  
Alain Berdeaux ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Ischemic Postconditioning ◽  
Myocardial Infarct Size ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Map Kinase Phosphatase

Ischemic postconditioning (IPCD) significantly reduces infarct size in healthy animals and protects the human heart. Because obesity is a major risk factor of cardiovascular diseases, the effects of IPCD were investigated in 8- to 10-wk-old leptin-deficient obese ( ob/ob) mice and compared with wild-type C57BL/6J (WT) mice. All animals underwent 30 min of coronary artery occlusion followed by 24 h of reperfusion associated or not with IPCD (6 cycles of 10-s occlusion, 10-s reperfusion). Additional mice were killed at 10 min of reperfusion for Western blotting. IPCD reduced infarct size by 58% in WT mice (33 ± 1% vs. 14 ± 3% for control and IPCD, respectively, P < 0.05) but failed to induce cardioprotection in ob/ob mice (53 ± 4% vs. 56 ± 5% for control and IPCD, respectively). In WT mice, IPCD significantly increased the phosphorylation of Akt (+77%), ERK1/2 (+41%), and their common target p70S6K1 (+153% at Thr389 and +57% at Thr421/Ser424). In addition, the phosphorylated AMP-activated protein kinase (AMPK)-to-total AMPK ratio was also increased by IPCD in WT mice (+64%, P < 0.05). This was accompanied by decreases in phosphatase and tensin homolog deleted on chromosome 10 (PTEN), MAP kinase phosphatase (MKP)-3, and protein phosphatase (PP)2C levels. In contrast, IPCD failed to increase the phosphorylation state of all these kinases in ob/ob mice, and the level of the three phosphatases was significantly increased. Thus, although IPCD reduces myocardial infarct size in healthy animals, its cardioprotective effect vanishes with obesity. The lack of enhanced phosphorylation by IPCD of Akt, ERK1/2, p70S6K1, and AMPK might partly explain the loss of cardioprotection in this experimental model of obese mice.

Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats

Pharmacology ◽  
2021 ◽  
Vol 106 (3-4) ◽  
pp. 189-201
Author(s):  
Shigang Qiao ◽  
Wen-jie Zhao ◽  
Huan-qiu Li ◽  
Gui-zhen Ao ◽  
Jian-zhong An ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Neonatal Rat ◽  
Ligand Docking ◽  
Autophagic Flux ◽  
Myocardial Infarct Size ◽  
Rat Cardiomyocytes

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

Abstract 300: Topical Application of IcyHot Reduces Myocardial Infarct Size in Rodents by a TRPA1-dependent Mechanism

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yun Wu ◽  
Yao Lu ◽  
Eric R Gross
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Calcium Influx ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Sprague Dawley ◽  
Area At Risk ◽  
Reactive Aldehydes

Toxic reactive aldehydes are formed during ischemia-reperfusion. The ion channel transient receptor potential ankryin 1 (TRPA1) is irreversibly modified by reactive aldehydes which can cause calcium influx and cell death. Here we tested whether topically applied creams containing a reversible TRPA1 agonist could reduce myocardial infarct size. Male Sprague-Dawley rats 8-10 weeks age were subjected to an in vivo myocardial ischemia-reperfusion model of 30 minutes of left anterior descending (LAD) coronary artery ischemia followed by 2 hours reperfusion. Prior to ischemia, rats were untreated or had 1g of cream applied to the abdomen. The creams tested were IcyHot, Bengay, Tiger Balm, or preparation H (Fig. 1A). Hearts were negatively stained for the area at risk and the infarct size was determined by using TTC staining (Fig. 1B). A subset of rodents prior to receiving IcyHot also received an intravenous bolus of the TRPA1 antagonist TCS-5861528 (1mg/kg) or AP-18 (1mg/kg). Interestingly, both IcyHot and Bengay reduced myocardial infarct size compared to untreated rodents (Fig. 1C and 1D IcyHot: 41±3%*, Bengay: 50±2%* versus control 62±1%, n=6/group, *P<0.001). Both preparation H and Tiger Balm failed to reduce myocardial infarct size (Tiger Balm: 63±2%, preparation H 59±2%). Giving a TRPA1 antagonist prior to IcyHot also blocked the reduction in infarct size. Our additional data also indicates the methyl salicylate (mint) in IcyHot and Bengay is the agent that limits myocardial infarct size. Since IcyHot and Bengay are safely used by humans, targeting TRPA1 by using products such as these could be quickly translatable and widely used to reduce ischemia-reperfusion injury.

Sign in / Sign up

Export Citation Format

Share Document