Cross-talk between calcineurin/NFAT and Jak/STAT signalling induces cardioprotective alphaB-crystallin gene expression in response to hypertrophic stimuli.
Among the stress proteins that are up-regulated in the heart due to imposed biomechanical stress, alphaB-crystallin (CryAB) is the most abundant and pivotal in rendering protection against stress-induced cell damage. Cardiomyocyte-specific expression of the CryAB gene was shown to be dependent upon an intact alphaBE4 cis-element located in the CryAB enhancer. To date, there is no evidence on the identity of regulatory proteins and associated signalling molecules that control CryAB expression in cardiomyocytes. In this study, we define a mechanism by which the calcineurin/NFAT and Jak/STAT pathways regulate CryAB gene expression in response to a hypertrophic agonist endothelin-1 (En-1), in hypertrophic hearts of mice with pressure overload (TAC) and in heart-targeted calcineurin over-expressing mice (MHC-CnA). We observed that in response to various hypertrophic stimuli the transcription factors NFAT, Nished and STAT3 form a dynamic ternary complex and interact with the alphaBE4 promoter element of the CryAB gene. Both dominant negative NFAT and AG490, an inhibitor of the Jak2 phosphorylation, inhibited CryAB gene transcription in transient transfection assays. AG490 was also effective in blocking the nuclear translocation of NFAT and STAT3 in cardiomyocytes treated with En-1. We observed a marked increase in CryAB gene expression in MHC-CnA mouse hearts accompanied with increased phosphorylation of STAT3. We conclude that hypertrophy-dependent CryAB gene expression can be attributed to a functional linkage between the Jak/STAT and calcineurin/NFAT signalling pathways, each of which are otherwise known to be involved independently in the deleterious outcome in cardiac hypertrophy.
Manukyan
Irena
I
Department of Anatomy and Cell Biology, Center for Cardiovascular and Muscle Research, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Galatioto
Josephine
J
Mascareno
Eduardo
E
Bhaduri
Sikha
S
Siddiqui
M A Q
MA
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011312:Pressure; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
D002316:Cardiotonic Agents; C525420:Cryab protein, mouse; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D038203:alpha-Crystallin B Chain; D053614:Janus Kinase 2; D019703:Calcineurin