PMID- 21478152 OWN - NLM STAT- MEDLINE DCOM- 20110728 LR - 20211203 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 286 IP - 21 DP - 2011 May 27 TI - Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. PG - 18465-73 LID - 10.1074/jbc.M110.200022 [doi] AB - Resistin has been suggested to be involved in the development of diabetes and insulin resistance. We recently reported that resistin is expressed in diabetic hearts and promotes cardiac hypertrophy; however, the mechanisms underlying this process are currently unknown. Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and beta-myosin heavy chain. Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-beta-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. Interestingly, these in vitro signaling pathways were also operative in vivo in ventricular tissues from adult rat hearts overexpressing resistin. These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. FAU - Kang, Soojeong AU - Kang S AD - Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. FAU - Chemaly, Elie R AU - Chemaly ER FAU - Hajjar, Roger J AU - Hajjar RJ FAU - Lebeche, Djamel AU - Lebeche D LA - eng GR - T32 HL007824/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110408 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Biomarkers) RN - 0 (Enzyme Inhibitors) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Irs1 protein, rat) RN - 0 (Resistin) RN - 114471-18-0 (Natriuretic Peptide, Brain) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.6.1.- (Ventricular Myosins) SB - IM MH - AMP-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism MH - Animals MH - Apoptosis/drug effects/genetics MH - Biomarkers/metabolism MH - Cardiomegaly/genetics/*metabolism/pathology MH - Cells, Cultured MH - Enzyme Inhibitors/pharmacology MH - Gene Expression Regulation/drug effects/genetics MH - Insulin Receptor Substrate Proteins/antagonists & inhibitors/genetics/*metabolism MH - Insulin Resistance/genetics MH - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism MH - Myocytes, Cardiac/*metabolism/pathology MH - Natriuretic Peptide, Brain/biosynthesis/genetics MH - Phosphorylation/drug effects/genetics MH - Rats MH - Rats, Sprague-Dawley MH - Resistin/genetics/*metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors/genetics/metabolism MH - *Signal Transduction MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism MH - Ventricular Myosins/biosynthesis/genetics PMC - PMC3099663 EDAT- 2011/04/12 06:00 MHDA- 2011/07/29 06:00 PMCR- 2012/05/27 CRDT- 2011/04/12 06:00 PHST- 2011/04/12 06:00 [entrez] PHST- 2011/04/12 06:00 [pubmed] PHST- 2011/07/29 06:00 [medline] PHST- 2012/05/27 00:00 [pmc-release] AID - S0021-9258(20)51104-6 [pii] AID - M110.200022 [pii] AID - 10.1074/jbc.M110.200022 [doi] PST - ppublish SO - J Biol Chem. 2011 May 27;286(21):18465-73. doi: 10.1074/jbc.M110.200022. Epub 2011 Apr 8.