scholarly journals Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

2018 ◽  
Vol 45 (5) ◽  
pp. 2107-2121 ◽  
Author(s):  
Chunyan Wang ◽  
Haobo Li ◽  
Sheng Wang ◽  
Xiaowen Mao ◽  
Dan Yan ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Troponin I ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Myocardial Infarct Size ◽  
H9c2 Cells ◽  
Knock Down ◽  
Non Invasive

Background/Aims: Protein kinase C(PKC)-ε activation is a mechanism of preconditioning cardioprotection but its role in repeated non-invasive limb ischemic preconditioning (rNLIP) mediated cardioprotection against myocardial ischemia/reperfusion (I/R) injury in diabetes is unknown. Methods: Eight-week streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats were subjected to I/R without or with rNLIP. In vitro, H9C2 cells were cultured with high glucose (HG) and subjected to hypoxia/re-oxygenation (H/R) without or with PKC-ε or STAT3 gene knock-down in the absence or presence of remote time hypoxia preconditioning (HPC). Results: Diabetic rats displayed larger post-ischemic myocardial infarct size and higher troponin-I release with concomitant cardiac PKC-ԑ overexpression and activation manifested as increased membrane translocation, while phosphorylated STAT3 (p-STAT3) and Akt (p-Akt) were lower compared to non-diabetic rats (all P<0.05). rNLIP reduced infarct size in both non-diabetic and diabetic rats. rNLIP reduced post-ischemic cardiac PKC-ԑ activation in diabetic while increased PKC-ԑ activation in non-diabetic rats, resulting in increased cardiac p-STAT3 and p-Akt. In H9C2 cells, HG increased PKC-ԑ expression and exacerbated post-H/R injury, accompanied with reduced p-STAT3 and p-Akt, which were all reverted by HPC. These HPC protective effects were abolished by either PKC-ԑ or STAT3 gene knock-down, except that PKC-ԑ gene knock-down reverted HG and H/R-induced reduction of p-STAT3. Conclusion: rNLIP attenuates diabetic heart I/R injury by mitigating HG-induced PKC-ԑ overexpression and, subsequently, activating STAT3.

Adenosine-enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion

2001 ◽  
Vol 280 (2) ◽  
pp. H591-H602 ◽  
Author(s):  
James D. McCully ◽  
Yoshiya Toyoda ◽  
Masahisa Uematsu ◽  
Robert D. Stewart ◽  
Sidney Levitsky
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Ischemia And Reperfusion ◽  
Infarct Size Reduction

Adenosine-enhanced ischemic preconditioning (APC) extends the cardioprotection of ischemic preconditioning (IPC) by both significantly decreasing myocardial infarct size and significantly enhancing postischemic functional recovery. In this study, the role of adenosine receptors during ischemia-reperfusion was determined. Rabbit hearts ( n = 92) were used for Langendorff perfusion. Control hearts were perfused for 180 min, global ischemia hearts received 30-min ischemia and 120-min reperfusion, and IPC hearts received 5-min ischemia and 5-min reperfusion before ischemia. APC hearts received a bolus injection of adenosine coincident with IPC. Adenosine receptor (A1, A2, and A3) antagonists were used with APC before ischemia and/or during reperfusion. GR-69019X (A1/A3) and MRS-1191/MRS-1220 (A3) significantly increased infarct size in APC hearts when administered before ischemia and significantly decreased functional recovery when administered during both ischemia and reperfusion ( P < 0.05 vs. APC). DPCPX (A1) administered either before ischemia and/or during reperfusion had no effect on APC cardioprotection. APC-enhanced infarct size reduction is modulated by adenosine receptors primarily during ischemia, whereas APC-enhanced postischemic functional recovery is modulated by adenosine receptors during both ischemia and reperfusion.

Abstract 411: Endogenous miRNA Induced By Ischemic Preconditioning Reduces Myocardial Infarct Size following Ischemia/Reperfusion In Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Chang Yin ◽  
Fadi N Salloum ◽  
Rakesh C Kukreja
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Coronary Artery Ligation ◽  
Myocardial Infarct Size ◽  
Artery Ligation ◽  
Buffer Control

BACKGROUND: Due to its short length (~24 nt) and non-coding nature, microRNA (miRNA) used to be regarded as “evolutionary transcriptional debris”. Recent evidence suggests that miRNA is a novel regulator for transcription and translation. It is known that brief episodes of ischemia during ischemic preconditioning (IPC) trigger complex genetic pro-survival program that results in modulation of several key proteins involved in protection against I/R injury. We hypothesized that miRNA synthesized during IPC is the potential mediator of such protection. METHODS / RESULTS : Hearts were isolated from 3 groups (n = 6/group) of adult ICR mice and subjected to the following treatments in Langendorff mode: 120 min of perfusion with Krebs-Henseleit buffer (control); 30 min global ischemia followed by 1 hr reperfusion (I/R); 2 cycles of 30 sec ischemia and 90 sec reperfusion followed by 30 min ischemia and 1 hr reperfusion (IPC). Infarct size (IS) was measured by triphenyl tetrazolium staining. IPC in the Langendorff model reduced IS from 29.7 ± 2.1% in the I/R hearts to 9.1 ± 1.8 % in the IPC group. This protection was associated with a significant induction of miRNA-1 (162 ± 13%), miRNA-21 (118 ± 6%), and miRNA-24 (46 ± 12%). To test its protective role, miRNA was extracted from 6 hearts following the IPC protocol; and then injected in vivo into the left ventricle wall in another group of 6 mice. Forty-eight hrs later, these mice were subjected to I/R injury in vivo by left coronary artery ligation for 30 min followed by reperfusion for 24 hr. In addition, a subset of mice was treated with miRNA inhibitors (methylated antisense miRNA) in conjunction with miRNA from IPC hearts. The results show that miRNA extracted from the IPC hearts reproduced a protective phenotype with significantly lower infarction (18.8 ± 2.5 %) in vivo as compared to saline-treated control (37.5 ± 2.2%). This protective effect was totally abolished by specific inhibitors of miRNA-1 and miRNA-21 (IS: 43.7 ± 2.1%). CONCLUSION : miRNA extracted from preconditioned hearts shows a protective role against I/R injury. The detection of miRNA in preconditioned hearts offers a novel strategy in cardioprotection. Further studies are needed to identify the gene targets by which miRNA generate protective phenotype.

Effects of selective inhibition of cytochrome P-450 ω-hydroxylases and ischemic preconditioning in myocardial protection

2006 ◽  
Vol 290 (2) ◽  
pp. H500-H505 ◽  
Author(s):  
Kasem Nithipatikom ◽  
Michael P. Endsley ◽  
Jeannine M. Moore ◽  
Marilyn A. Isbell ◽  
John R. Falck ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Canine Heart ◽  
Area At Risk ◽  
Cytochrome P 450

Cytochrome P-450 (CYP) ω-hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP ω-hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP ω-hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 ± 1.0% (control), 9.6 ± 1.5% (0.40 mg/kg DDMS), 4.0 ± 2.0% (0.81 mg/kg DDMS), P < 0.01]. In addition, 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 ± 1.3% (0.032 mg/kg 20-HEDE) and 5.9 ± 1.9% (0.064 mg/kg 20-HEDE), P < 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 ± 2.8% (IPC) to 2.5 ± 1.4% (0.81 mg/kg DDMS), P < 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP ω-hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP ω-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.

Abstract 15: Remote Ischemic Preconditioning Confers Late Protection Against Myocardial Ischemia-Reperfusion Injury in Mice by Upregulating Interleukin-10

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zheqing Cai ◽  
Nirmal Parajuli ◽  
Xiaoxu Zheng ◽  
Lewis Becker
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Gastrocnemius Muscle ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Late Phase ◽  
Remote Ischemic Preconditioning ◽  
Myocardial Infarct Size ◽  
Stat3 Phosphorylation

Remote ischemic preconditioning (RIPC) induces a prolonged late phase of multi-organ protection against ischemia-reperfusion (IR) injury. In the present study, we tested the hypothesis that RIPC confers late protection against myocardial IR injury by upregulating expression of IL-10. Mice were exposed to lower limb RIPC or sham leg ischemia. After 24 h, mice with RIPC demonstrated decreased myocardial infarct size and improved cardiac contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120), accompanied by increased phosphorylation of Akt and eNOS in the heart. These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies. Moreover, in IL-10 KO mice, RIPC was no longer able to provide cardioprotection against IR injury. IL-10 receptors were expressed in cardiomyocytes under basal conditions. Stimulation with exogenous IL-10 increased Akt phosphorylation and decreased myocardial infarct size after I-30/R-120 in isolated perfused hearts. Wildtype mice with RIPC demonstrated increased plasma IL-10 levels, while in the preconditioned gastrocnemius muscle, the phosphatase PTEN was inactivated and expression of IL-10 was increased through Stat3. Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and IL-10 protein expression in the gastrocnemius muscle. Taken together, these results suggest that RIPC induces late protection against myocardial IR injury by increasing expression of IL-10 in the remote muscle, followed by release of IL-10 into the circulation, and activation of protective signaling pathways in the heart. This study provides a scientific basis for the use of RIPC to confer systemic protection against IR injury.

scholarly journals Shen-Fu Injection Preconditioning Inhibits Myocardial Ischemia-Reperfusion Injury in Diabetic Rats: Activation of eNOS via the PI3K/Akt Pathway

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Yang Wu ◽  
Zhong-yuan Xia ◽  
Qing-tao Meng ◽  
Jie Zhu ◽  
Shaoqing Lei ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Protein Expression ◽  
Infarct Size ◽  
Sham Group ◽  
Kinase Inhibitor ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

The aim of this paper is to investigate whether Shen-fu injection (SFI), a traditional Chinese medicine, could attenuate myocardial ischemia-reperfusion (MI/R) injury in diabetes. Streptozotocin-induced diabetic rats were randomly assigned to the Sham, I/R, SFI preconditioning, and SFI plus wortmannin (a phosphatidylinositol 3-kinase inhibitor) groups. After the treatment, hearts were subjected to 30 min of coronary artery occlusion and 2 h reperfusion except the Sham group. Myocardial infarct size and cardiomyocytes apoptosis were increased significantly in MI/R group as compared with the Sham group. SFI preconditioning significantly decreased infarct size, apoptosis, caspase-3 protein expression, MDA level in myocardial tissues, and plasma level of CK and LDH but increased p-Akt, p-eNOS, bcl-2 protein expression, and SOD activity compared to I/R group. Moreover, SFI-induced cardioprotection was abolished by wortmannin. We conclude that SFI preconditioning protects diabetic hearts from I/R injury via PI3K/Akt-dependent pathway.

scholarly journals Melatonin postconditioning combined with sitagliptin exerts full cardioprotection in diabetic hearts of aged rats through an AMPK-dependent mechanism

2021 ◽  
Vol 73 (1) ◽  
pp. 83-92
Author(s):  
Ronggang Song ◽  
Jing Ren ◽  
Junxia Sun ◽  
Ming Li
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Myocardial Infarct Size ◽  
Aged Rats ◽  
Sprague Dawley ◽  
Oxidative Markers ◽  
Mitochondrial Superoxide ◽  
Compound C

The presence of multiple comorbidities in patients facing myocardial ischemia-reperfusion (IR) injury is the main obstacle for cardioprotection. This study investigated the effect of melatonin postconditioning combined with sitagliptin pretreatment on cardioprotection in diabetic aged rats by evaluating oxidative stress, apoptosis and involvement of the AMPK/SIRT1 pathway. The type-2 high-fat/streptozotocin experimental model in aged Sprague-Dawley rats (n=78) was used. The animals underwent left coronary occlusion for 30 min, followed by 3 h reperfusion. Diabetic rats were pretreated with sitagliptin (20 mg/kg, i.p.) and received melatonin (10 mg/kg, i.p.) early in reperfusion. Myocardial infarct size, histological changes, oxidative markers, mitochondrial reactive oxygen species (mitoROS) and expression of proteins regulating apoptosis and AMPK/SIRT1 activity were measured. The infarct size-sparing effect of the combination of melatonin plus sitagliptin was greater than that observed in individual treatments (P<0.01). Combination therapy significantly reduced IRinduced elevation of 8-isoprostane, mitoROS and proapoptotic proteins Bax and cleaved caspase-3, and increased IR-induced downregulation of mitochondrial superoxide-dismutase, glutathione, anti-apoptotic protein Bcl2, phosphorylated AMPK and SIRT1 (P<0.01, P<0.001). Inhibition of AMPK via compound-C completely reversed combination-induced cardioprotection. Thus, improving cardiac antioxidative and antiapoptotic responses via upregulation of AMPK/SIRT1 activity may represent a central mechanism through which melatonin plus sitagliptin attenuate myocardial IR injury in diabetic-aged rats.

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