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

• Published in: The Journal of biological chemistry Vol. 286; no. 21; pp. 18465 - 18473
• Main Authors: Kang, Soojeong, Chemaly, Elie R., Hajjar, Roger J., Lebeche, Djamel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.05.2011; American Society for Biochemistry and Molecular Biology
• Subjects: AMP-activated Kinase (AMPK); AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Apoptosis - drug effects; Apoptosis - genetics; Biomarkers - metabolism; Cardiac Hypertrophy; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomyocyte; Cells, Cultured; Diabetes; Diabetic Cardiomyopathy; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Transfer; Insulin Receptor Substrate Proteins - antagonists & inhibitors; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Insulin Resistance - genetics; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Molecular Bases of Disease; mTOR, JNK Signaling; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Natriuretic Peptide, Brain - biosynthesis; Natriuretic Peptide, Brain - genetics; Phosphorylation - drug effects; Phosphorylation - genetics; Rats; Rats, Sprague-Dawley; Resistin; Resistin - genetics; Resistin - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Ventricular Myosins - biosynthesis; Ventricular Myosins - genetics; Cardiomyocyte; Insulin Resistance; AMP-activated Kinase (AMPK); Gene Transfer; Diabetes; mTOR, JNK Signaling; Cardiac Hypertrophy; Diabetic Cardiomyopathy; Resistin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.200022

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, [3H]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 p70S6K, 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/p70S6K and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways.