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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.
J Biol Chem 2011; 286(21):18465-73JB

Abstract

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 β-myosin heavy chain. Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-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.

Authors+Show Affiliations

Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21478152

Citation

Kang, Soojeong, et al. "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." The Journal of Biological Chemistry, vol. 286, no. 21, 2011, pp. 18465-73.
Kang S, Chemaly ER, Hajjar RJ, et al. 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. J Biol Chem. 2011;286(21):18465-73.
Kang, S., Chemaly, E. R., Hajjar, R. J., & Lebeche, D. (2011). 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. The Journal of Biological Chemistry, 286(21), pp. 18465-73. doi:10.1074/jbc.M110.200022.
Kang S, et al. 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. J Biol Chem. 2011 May 27;286(21):18465-73. PubMed PMID: 21478152.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kang,Soojeong, AU - Chemaly,Elie R, AU - Hajjar,Roger J, AU - Lebeche,Djamel, Y1 - 2011/04/08/ PY - 2011/4/12/entrez PY - 2011/4/12/pubmed PY - 2011/7/29/medline SP - 18465 EP - 73 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 286 IS - 21 N2 - 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 β-myosin heavy chain. Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/21478152/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_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=21478152 DB - PRIME DP - Unbound Medicine ER -