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

Soojeong Kang,Roger J. Hajjar,Djamel Lebeche,Elie R. Chemaly

doi:10.1074/jbc.m110.200022

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.

Highlights

Cardiac hypertrophy, defined as an increase in ventricular mass resulting from increased cardiomyocyte size, is an adaptive response of the heart to increased hemodynamic load arising from a variety of conditions, including exercise, hypertension, and valvular disease [4]
MTOR/p70S6K Pathway Inhibition Reduces Resistin-induced Hypertrophic Changes in Neonatal rat ventricular myocytes (NRVM)—To further study mammalian target of rapamycin (mTOR) signaling in resistin-induced cardiac hypertrophy, lysates from NRVM treated with Ad.rRetn in the presence or absence of rapamycin (100 nM) were subjected to immunoblot analysis using an antibody against mTOR phosphorylated at Ser-2448 or insulin receptor substrate 1 (IRS1) phosphorylated at Ser-636/Ser-639
Resistin Modulates the ASK1/Jun N-terminal Kinase (JNK)/IRS1 Pathway, and JNK Inhibition Diminishes Resistin-induced IRS1 Serine Phosphorylation in NRVM—To further elucidate the involvement of other mechanisms in the action of resistin on cardiac hypertrophy and insulin resistance, we investigated the activation of JNK in NRVM infected with Ad.rRetn or Ad.␤Gal

Summary

Introduction

Cardiac hypertrophy, defined as an increase in ventricular mass resulting from increased cardiomyocyte size, is an adaptive response of the heart to increased hemodynamic load arising from a variety of conditions, including exercise, hypertension, and valvular disease [4]. We present evidence that resistin promotes cardiac hypertrophy and myocardial insulin resistance through activation of the AMPK/mTOR/ p70S6K and ASK1/JNK/IRS1 signaling pathways.

Results

Conclusion