Cardioprotective Effect of the SDF-1α/CXCR4 Axis in Ischemic Postconditioning in Isolated Rat Hearts

김정수,장영호,김준홍,박용현,황선애,김준,이성률,Zhelong Xu,반창일,안교한,전국진 대한심장학회 2017 Korean Circulation Journal Vol.47 No.6

Background and Objectives: Information about the role of the stromal cell-derived factor-1α (SDF-1α)/chemokine receptor type 4 (CXCR4) axis in ischemic postconditioning (IPOC) is currently limited. We hypothesized that the SDF-1α/CXCR4 signaling pathway is directly involved in the cardioprotective effect of IPOC. Methods: Isolated rat hearts were divided into four groups. The control group was subjected to 30-min of regional ischemia and 2-hour of reperfusion (n=12). The IPOC group was induced with 6 cycles of 10-second reperfusion and 10-second global ischemia (n=8) in each cycle. The CXCR4 antagonist, AMD3100, was applied before reperfusion in the IPOC group (AMD+IPOC group, n=11) and control group (AMD group, n=9). Hemodynamic changes with electrocardiography were monitored and infarct size was measured. The SDF-1α, lactate dehydrogenase (LDH) and creatine kinase (CK) concentrations in perfusate were measured. We also analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation state expression. Results: IPOC significantly reduced infarct size, but AMD3100 attenuated the infarct reducing effect of IPOC. IPOC significantly decreased LDH and CK, but these effects were reversed by AMD3100. ERK1/2 and Akt phosphorylation increased with IPOC and these effects were blocked by AMD3100. Conclusion: Based on the results of this study, SDF-1α/CXCR4 signaling may be involved in IPOC cardioprotection and this signaling pathway couples to the ERK1/2 and Akt pathways.

Polyphenol (-)-Epigallocatechin Gallate during Ischemia Limits Infarct Size Via Mitochondrial KATP Channel Activation in Isolated Rat Hearts

송대규,장영호,김준홍,전국진,이덕희,Zhelong Xu 대한의학회 2010 Journal of Korean medical science Vol.25 No.3

Polyphenol (-)-epigallocatechin gallate (EGCG), the most abundant catechin of green tea, appears to attenuate myocardial ischemia/reperfusion injury. We investigated the involvement of ATP-sensitive potassium (KATP) channels in EGCG-induced cardioprotection. Isolated rat hearts were subjected to 30 min of regional ischemia and 2 hr of reperfusion. EGCG was perfused for 40 min, from 10 min before to the end of index ischemia. A nonselective KATP channel blocker glibenclamide (GLI) and a selective mitochondrial KATP (mKATP) channel blocker 5-hydroxydecanoate (HD) were perfused in EGCG-treated hearts. There were no differences in coronary flow and cardiodynamics including heart rate, left ventricular developed pressure, rate-pressure product, +dP/dtmax, and -dP/dtmin throughout the experiments among groups. EGCG-treatment significantly reduced myocardial infarction (14.5±2.5% in EGCG 1 mM and 4.0±1.7% in EGCG 10 mM, P<0.001 vs. control 27.2±1.4%). This antiinfarct effect was totally abrogated by 10 mM GLI (24.6±1.5%, P<0.001 vs. EGCG). Similarly, 100 mM HD also aborted the anti-infarct effect of EGCG (24.1±1.2%, P<0.001 vs. EGCG ). These data support a role for the KATP channels in EGCG-induced cardioprotection. The mKATP channels play a crucial role in the cardioprotection by EGCG.

Cardiodynamics and Infarct Size in Regional and Global Ischemic Isolated Heart Model: Comparison of 1 Hour and 2 Hours Reperfusion

김준홍,김준,박용현,전국진,김정수,Young Ho Jang,이미영,Zhelong Xu 대한심장학회 2012 Korean Circulation Journal Vol.42 No.9

Background and Objectives: We investigated whether 1 hour reperfusion is enough to assess cardiodynamics and infarct size in both regional ischemia (RI) and global ischemia (GI) in isolated rat heart models. Materials and Methods: Hearts were randomly assigned to one of the following groups (each n=14): 1) Sham hearts for 1 hour; 2)Sham hearts for 2 hours; 3) 30 minutes RI followed by 1 hour reperfusion; 4) 30 minutes of RI followed by 2 hours reperfusion; 5) 30minutes GI followed by 1 hour reperfusion; and 6) 30 minutes GI followed by 2 hours reperfusion. Results: There were no significant differences in infarct size between 1 hour and 2 hours reperfusion in both RI and GI. Left ventricular developed pressure was significantly decreased at both 1 hour and 2 hours reperfusion in groups of RI and GI compared to baseline (p<0.01). Rate-pressure product and +dP/dt max also significantly decreased compared to baseline level at both 1 hour and 2 hours reper-fusion in groups of RI and GI (p<0.05). Conclusion: There was no significant difference in infarct size between 1 hour and 2 hours reperfusion in groups of RI and GI. Cardiody-namic variables measured at 1 hour and 2 hours reperfusion significantly decreased compared to baseline level. Our data suggests that reperfusion of 1 hour is sufficient to assess cardiodynamics in both regional and global ischemic isolated hearts model.

NecroX-5 suppresses sodium nitroprusside-induced cardiac cell death through inhibition of JNK and caspase-3 activation.

Lee, Sung Ryul,Lee, Seon Joong,Kim, Soon Ha,Ko, Kyung Soo,Rhee, Byoung Doo,Xu, Zhelong,Kim, Nari,Han, Jin Published for the International Federation for Cel 2014 Cell biology international Vol.38 No.6

<P>Although sodium nitroprusside (SNP) is an effective hypotensive drug and is often used in pediatric intensive care units and to treat acute heart failure, clinical application of SNP is limited by its cardiotoxicity. NecroX-5 (NX-5) was recently developed and has the capacity to inhibit necrotic cell death. No current literature addresses whether NX-5 suppresses SNP-induced cell death or its mechanism of action. We have investigated the protective role of NX-5 against SNP-induced cell death in cardiomyocyte-like H9c2 cells. SNP treatment induced severe cell death, possibly through phosphorylation of stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) and activation of the apoptotic signaling pathway, including downregulation of Bcl-2 and cleavage of caspase-3. However, NX-5 suppresses SNP-induced cell death through inhibition of JNK activation and suppression of both downregulation of Bcl-2 protein expression and caspase-3 cleavage. These findings will provide insights and facilitate development of antidotes to SNP toxicity in cardiac cells.</P>

The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling

Sung Ryul Lee,Su Jin Noh,Julius Ryan Pronto,Yu Jeong Jeong,Hyoung Kyu Kim,In Sung Song,Zhelong Xu,Hyog Young Kwon,Se Chan Kang,Eun-Hwa Sohn,Kyung Soo Ko,Byoung Doo Rhee,Nari Kim,Jin Han 대한생리학회-대한약리학회 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.5

Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn²⁺) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc’s critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn²⁺ activity has been presumed to parallel the degree of calcium’s participation in cellular processes. Whole body and cellular Zn²⁺ levels are largely regulated by metallothioneins (MTs), Zn²⁺ importers (ZIPs), and Zn²⁺ transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn²⁺. However, these regulatory actions of Zn²⁺ are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn²⁺ levels, Zn²⁺-mediated signal transduction, impacts of Zn²⁺ on ion channels and mitochondrial metabolism, and finally, the implications of Zn²⁺ in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn²⁺.

Polyphenol (-)-Epigallocatechin Gallate during Ischemia Limits Infarct Size Via Mitochondrial K _ATP Channel Activation in Isolated Rat Hearts

Song, Dae-Kyu,Jang, Youngho,Kim, June Hong,Chun, Kook-Jin,Lee, Deokhee,Xu, Zhelong The Korean Academy of Medical Sciences 2010 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.25 No.3

<P>Polyphenol (-)-epigallocatechin gallate (EGCG), the most abundant catechin of green tea, appears to attenuate myocardial ischemia/reperfusion injury. We investigated the involvement of ATP-sensitive potassium (K<SUB>ATP</SUB>) channels in EGCG-induced cardioprotection. Isolated rat hearts were subjected to 30 min of regional ischemia and 2 hr of reperfusion. EGCG was perfused for 40 min, from 10 min before to the end of index ischemia. A nonselective K<SUB>ATP</SUB> channel blocker glibenclamide (GLI) and a selective mitochondrial K<SUB>ATP</SUB> (mK<SUB>ATP</SUB>) channel blocker 5-hydroxydecanoate (HD) were perfused in EGCG-treated hearts. There were no differences in coronary flow and cardiodynamics including heart rate, left ventricular developed pressure, rate-pressure product, +dP/dt<SUB>max</SUB>, and -dP/dt<SUB>min</SUB> throughout the experiments among groups. EGCG-treatment significantly reduced myocardial infarction (14.5±2.5% in EGCG 1 µM and 4.0±1.7% in EGCG 10 µM, <I>P</I><0.001 vs. control 27.2±1.4%). This anti-infarct effect was totally abrogated by 10 µM GLI (24.6±1.5%, <I>P</I><0.001 vs. EGCG). Similarly, 100 µM HD also aborted the anti-infarct effect of EGCG (24.1±1.2%, <I>P</I><0.001 vs. EGCG ). These data support a role for the K<SUB>ATP</SUB> channels in EGCG-induced cardioprotection. The mK<SUB>ATP</SUB> channels play a crucial role in the cardioprotection by EGCG.</P>

The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling

Lee, Sung Ryul,Noh, Su Jin,Pronto, Julius Ryan,Jeong, Yu Jeong,Kim, Hyoung Kyu,Song, In Sung,Xu, Zhelong,Kwon, Hyog Young,Kang, Se Chan,Sohn, Eun-Hwa,Ko, Kyung Soo,Rhee, Byoung Doo,Kim, Nari,Han, Jin The Korean Society of Pharmacology 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.5

Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc ($Zn^{2+}$) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc's critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of $Zn^{2+}$ activity has been presumed to parallel the degree of calcium's participation in cellular processes. Whole body and cellular $Zn^{2+}$ levels are largely regulated by metallothioneins (MTs), $Zn^{2+}$ importers (ZIPs), and $Zn^{2+}$ transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of $Zn^{2+}$. However, these regulatory actions of $Zn^{2+}$ are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular $Zn^{2+}$ levels, $Zn^{2+}$-mediated signal transduction, impacts of $Zn^{2+}$ on ion channels and mitochondrial metabolism, and finally, the implications of $Zn^{2+}$ in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of $Zn^{2+}$.

Kobophenol A inhibits sodium nitroprusside-induced cardiac H9c2 cell death through suppressing activation of JNK and preserving mitochondrial anti-apoptotic Bcl-2 and Mcl-1.

Lee, Sung Ryul,Kwak, Jong Hwan,Noh, Su Jin,Pronto, Julius Ryan,Ko, Kyung Soo,Rhee, Byoung Doo,Xu, Zhelong,Kim, Nari,Han, Jin Pharmaceutical Society of Japan 2014 Chemical & pharmaceutical bulletin Vol.62 No.7

<P>Sodium nitroprusside (SNP) releases nitric oxide (NO), a powerful vasodilator, and thus widely used in intensive care unit for treating hypertension emergency. However, cardiac toxicity after SNP administration is a clinical problem. For finding a natural compound that suppressing SNP-induced cardiac toxicity, we tested the protective potential of kobophenol A (Kob A), purified from the root of Caragana sinica, against the toxic effects of SNP. The severe cardiac H9c2 cell death was induced by SNP (2?mM) treatment. Kob A ameliorated SNP-induced cardiac H9c2 cell death, and this protective effect of Kob A may be related to the inhibition of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase activation following SNP administration. In addition, the downregulation of cellular Bcl-2 and Mcl-1 levels by SNP exposure was strongly abrogated in the presence of Kob A. These biological properties of Kob A might provide insights into developing new cardioprotectant against SNP-induced cardiac cell death.</P>