Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4

Srikanth Koneru, Suresh Varma Penumathsa, Mahesh Thirunavukkarasu, Samson Mathews Samuel, Lijun Zhan, Zhihua Han, Gautam Maulik, Dipak K. Das, Nilanjana Maulik

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Abstract

Reactive oxygen species (ROS) generated during ischemia-reperfusion (I/R) enhance myocardial injury, but brief periods of myocardial ischemia followed by reperfusion [ischemic preconditioning (IP)] induce cardioprotection. Ischemia is reported to stimulate glucose uptake through the translocation of GLUT-4 from the intracellular vesicles to the sarcolemma. In the present study we demonstrated involvement of ROS in IP-mediated GLUT-4 translocation along with increased expression of caveolin (Cav)-3, phospho (p)-endothelial nitric oxide synthase (eNOS), p-Akt, and decreased expression of Cav-1. The rats were divided into the following groups: 1) control sham, 2) N-acetyl-L-cysteine (NAC, free radical scavenger) sham (NS), 3) I/R, 4) IP + I/R (IP), and 5) NAC + IP (IPN). IP was performed by four cycles of 4 min of ischemia and 4 min of reperfusion followed by 30 min of ischemia and 3, 24, 48 h of reperfusion, depending on the protocol. Increased mRNA expression of GLUT-4 and Cav-3 was observed after 3 h of reperfusion in the IP group compared with other groups. IP increased expression of GLUT-4, Cav-3, and p-AKT and p-eNOS compared with I/R. Coimmunoprecipitation demonstrated decreased association of Cav-1/eNOS in the IP group compared with the I/R group. Significant GLUT-4 and Cav-3 association was also observed in the IP group. This association was disrupted when NAC was used in conjunction with IP. It clearly documents a significant role of ROS signaling in Akt/eNOS/Cav-3-mediated GLUT-4 translocation and association in IP myocardium. In conclusion, we demonstrated a novel redox mechanism in IP-induced eNOS and GLUT-4 translocation and the role of caveolar paradox in making the heart euglycemic during the process of ischemia, leading to myocardial protection in a clinically relevant rat ischemic model.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number5
DOIs
Publication statusPublished - 1 May 2007
Externally publishedYes

Fingerprint

Caveolins
Ischemic Preconditioning
Nitric Oxide Synthase Type III
Oxidation-Reduction
Caveolin 3
Reperfusion
Ischemia
Caveolin 1
Reactive Oxygen Species
montirelin
Myocardial Reperfusion Injury
Sarcolemma
Free Radical Scavengers
Acetylcysteine

Keywords

  • Akt
  • Caveolin-1
  • Caveolin-3
  • Endothelial nitric oxide synthase
  • Glucose transporter 4
  • Nitric oxide
  • Redox signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. / Koneru, Srikanth; Penumathsa, Suresh Varma; Thirunavukkarasu, Mahesh; Mathews Samuel, Samson; Zhan, Lijun; Han, Zhihua; Maulik, Gautam; Das, Dipak K.; Maulik, Nilanjana.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 292, No. 5, 01.05.2007.

Research output: Contribution to journalArticle

Koneru, Srikanth ; Penumathsa, Suresh Varma ; Thirunavukkarasu, Mahesh ; Mathews Samuel, Samson ; Zhan, Lijun ; Han, Zhihua ; Maulik, Gautam ; Das, Dipak K. ; Maulik, Nilanjana. / Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 292, No. 5.
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AU - Thirunavukkarasu, Mahesh

AU - Mathews Samuel, Samson

AU - Zhan, Lijun

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AU - Maulik, Gautam

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AB - Reactive oxygen species (ROS) generated during ischemia-reperfusion (I/R) enhance myocardial injury, but brief periods of myocardial ischemia followed by reperfusion [ischemic preconditioning (IP)] induce cardioprotection. Ischemia is reported to stimulate glucose uptake through the translocation of GLUT-4 from the intracellular vesicles to the sarcolemma. In the present study we demonstrated involvement of ROS in IP-mediated GLUT-4 translocation along with increased expression of caveolin (Cav)-3, phospho (p)-endothelial nitric oxide synthase (eNOS), p-Akt, and decreased expression of Cav-1. The rats were divided into the following groups: 1) control sham, 2) N-acetyl-L-cysteine (NAC, free radical scavenger) sham (NS), 3) I/R, 4) IP + I/R (IP), and 5) NAC + IP (IPN). IP was performed by four cycles of 4 min of ischemia and 4 min of reperfusion followed by 30 min of ischemia and 3, 24, 48 h of reperfusion, depending on the protocol. Increased mRNA expression of GLUT-4 and Cav-3 was observed after 3 h of reperfusion in the IP group compared with other groups. IP increased expression of GLUT-4, Cav-3, and p-AKT and p-eNOS compared with I/R. Coimmunoprecipitation demonstrated decreased association of Cav-1/eNOS in the IP group compared with the I/R group. Significant GLUT-4 and Cav-3 association was also observed in the IP group. This association was disrupted when NAC was used in conjunction with IP. It clearly documents a significant role of ROS signaling in Akt/eNOS/Cav-3-mediated GLUT-4 translocation and association in IP myocardium. In conclusion, we demonstrated a novel redox mechanism in IP-induced eNOS and GLUT-4 translocation and the role of caveolar paradox in making the heart euglycemic during the process of ischemia, leading to myocardial protection in a clinically relevant rat ischemic model.

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