Author(s): Xuan YT, Guo Y, Han H, Zhu Y, Bolli R
The goal of this study was to determine the role of the Janus tyrosine kinase (JAK)-signal transducers and activators of transcription (STAT) pathway in the late phase of ischemic preconditioning (PC). A total of 230 mice were used. At 5 min after ischemic PC (induced with six cycles of 4-min coronary occlusion/4-min reperfusion), immunoprecipitation with anti-phosphotyrosine (anti-pTyr) antibodies followed by immunoblotting with anti-JAK antibodies revealed increased tyrosine phosphorylation of JAK1 (+257 +/- 53%) and JAK2 (+238 +/- 35%), indicating rapid activation of these two kinases. Similar results were obtained by immunoblotting with anti-pTyr-JAK1 and anti-pTyr-JAK2 antibodies. Western analysis with anti-pTyr-STAT antibodies demonstrated a marked increase in nuclear pTyr-STAT1 (+301 +/- 61%) and pTyr-STAT3 (+253 +/- 60%) 30 min after ischemic PC, which was associated with redistribution of STAT1 and STAT3 from the cytosolic to the nuclear fraction and with an increase in STAT1 and STAT3 gamma-IFN activation site DNA-binding activity (+606 +/- 64%), indicating activation of STAT1 and STAT3. No nuclear translocation or tyrosine phosphorylation of STAT2, STAT4, STAT5A, STAT5B, or STAT6 was observed. Pretreatment with the JAK inhibitor AG-490 20 min before the six occlusion/reperfusion cycles blocked the enhanced tyrosine phosphorylation of JAK1 and JAK2 and the increased tyrosine phosphorylation, nuclear translocation, and enhanced DNA-binding activity of STAT1 and STAT3. The same dose of AG-490 abrogated the protection against myocardial infarction and the concomitant up-regulation of inducible NO synthase (iNOS) protein and activity observed 24 h after ischemic PC. Taken together, these results demonstrate that ischemic PC induces isoform-selective activation of JAK1, JAK2, STAT1, and STAT3, and that ablation of this response impedes the up-regulation of iNOS and the concurrent acquisition of ischemic tolerance. This study demonstrates that the JAK-STAT pathway plays an essential role in the development of late PC. The results reveal a signaling mechanism that underlies the transcriptional up-regulation of the cardiac iNOS gene and the adaptation of the heart to ischemic stress.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/11481471
Author(s): Dhingra R, Vasan RS
Author(s): Fox KA, Bergmann SR, Sobel BE
Author(s): Luca MC, Liuni A, Muxel S, Münzel T, Forconi S, et al.
Author(s): Xia Z, Xia R, Lan HT, Luo T, Tang QZ, et al.
Author(s): Fan Q, Yang XC, Liu Y, Wang LF, Liu SH, et al.
Author(s): Huang Z, Zhong X, Irwin MG, Ji S, Wong GT, et al.
Author(s): Xia Z, Wang F, Luo T
Author(s): Gong JS, Yao YT, Fang NX, Huang J, Li LH
Author(s): Liu C, Dai R, Yu R, Xu J
Author(s): Wang T, Qiao S, Lei S, Liu Y, Ng KF, et al.
Author(s): Nie R, Zhong X, Xia Z
Author(s): Balakumar P, Sharma NK
Author(s): Tai W, Shi E, Yan L, Jiang X, Ma H, et al.
Author(s): Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC
Author(s): Buja LM
Author(s): Kim DH, Kim YJ, Chang SA, Lee HW, Kim HN, et al.
Author(s): Greer EL, Brunet A
Author(s): Vogt PK, Jiang H, Aoki M
Author(s): Maiese K, Chong ZZ, Shang YC, Hou J
Author(s): Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE
Author(s): Zhao X, Gan L, Pan H, Kan D, Majeski M, et al.
Author(s): Van Der Heide LP, Hoekman MF, Smidt MP
Author(s): Oellerich MF, Potente M
Author(s): Ferdous A, Battiprolu PK, Ni YG, Rothermel BA, Hill JA
Author(s): Ronnebaum SM, Patterson C
Author(s): Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, et al.
Author(s): Puthanveetil P, Zhang D, Wang Y, Wang F, Wan A, et al.
Author(s): Puthanveetil P, Wang Y, Wang F, Kim MS, Abrahani A, et al.
Author(s): Puthanveetil P, Wang Y, Zhang D, Wang F, Kim MS, et al.
Author(s): Miki T, Itoh T, Sunaga D, Miura T
Author(s): Akiyama N, Okumura K, Watanabe Y, Hashimoto H, Ito T, et al.
Author(s): Nakada T, Kwee IL
Author(s): Depre C, Vanoverschelde JL, Taegtmeyer H
Author(s): Wijns W, Vatner SF, Camici PG
Author(s): Leung AA, Eurich DT, Lamb DA, Majumdar SR, Johnson JA, et al.
Author(s): Huffmyer J, Raphael J
Author(s): Tremblay ML, Giguère V
Author(s): Steinberg SF
Author(s): Furuyama T, Kitayama K, Yamashita H, Mori N
Author(s): Ding M, Rzucidlo EM, Davey JC, Xie Y, Liu R, et al.
Author(s): Gross DN, van den Heuvel AP, Birnbaum MJ
Author(s): Marfella R, Di Filippo C, Esposito K, Nappo F, Piegari E, et al.
Author(s): Tzivion G, Dobson M, Ramakrishnan G
Author(s): Kim MS, Wang F, Puthanveetil P, Kewalramani G, Innis S, et al.
Author(s): Parisi Q, Biondi-Zoccai GG, Abbate A, Santini D, Vasaturo F, et al.
Author(s): Andrews NP, Prasad A, Quyyumi AA
Author(s): Brunet J, Boily MJ, Cordeau S, Des Rosiers C
Author(s): Hsu CP, Zhai P, Yamamoto T, Maejima Y, Matsushima S, et al.
Author(s): Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, et al.
Author(s): Pitocco D, Zaccardi F, Di Stasio E, Romitelli F, Santini SA, et al.
Author(s): Mehra A, Shotan A, Ostrzega E, Hsueh W, Vasquez-Johnson J, et al.
Author(s): Bauters C, Lamblin N, Mc Fadden EP, Van Belle E, Millaire A, et al.
Author(s): Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, et al.
Author(s): Kok BP, Brindley DN
Author(s): Philip-Couderc P, Tavares NI, Roatti A, Lerch R, Montessuit C, et al.
Author(s): Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM
Author(s): Zhan L, Wang T, Li W, Xu ZC, Sun W, et al.
Author(s): Somers SJ, Frias M, Lacerda L, Opie LH, Lecour S