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

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, 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.

LKB1/AMPK pathway mediates resistin-induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

“…Resistin can be regulated by a number of cytokines, including endothelin (ET), insulin, insulin-like growth factors (IGFs), and peroxisome proliferator-activated receptor (PPAR). Furthermore, resistin has been reported to induce cardiac hypertrophy through a number of signaling pathways, such as extracellular signal-regulated kinases (ERK), AMPK/mammalian target of rapamycin (mTOR), and the c-Jun NH (2)-terminal kinase (JNK)/insulin receptor substrate 1 (IRS1) pathway (11,13). The underlying molecular mechanisms by which resistin induces cardiac hypertrophy are still not completely understood.…”

Insulin Resistance in SHR/NDmc-cp Rats Correlates with Enlarged Perivascular Adipocytes and Endothelial Cell Dysfunction in Skeletal Muscle

“…Considering that the perivascular adipocytes in the gastrocnemius were mostly atrophied in STZ-treated WKY rats, excess insulin secretion was likely responsible for excess fat accumulation in the perivascular adipocytes in SHR/NDmc-cp rats. Interestingly, expression of the resistin, an adipocytokine that inhibits insulin signaling by associating with insulin receptor (26)(27)(28), was much higher in SHR/NDmc-cp rats than in the other groups, whereas no significant differences were found for adiponectin, an adipocytokine associated with insulin sensitivity. Resistin is involved in inactivation of endothelial function (29), and in impaired glucose metabolism in myocytes and adipocytes (30,31).…”

Diabetic Cardiomyopathy. Resistin: A Control of a Myocardial Hypertrophy

“…В сердце резистин способен активно стимулировать в фибробластах миокарда экспрессию мРНК металло-протеазы-2 и металлопротеазы-9, в то же время по-давляя экспрессию мРНК их тканевых внеклеточных ин-гибиторов ТИМП-1 и ТИМП-2. Воздействуя, таким образом, на обмен соединительно-тканных белков сердечной мышцы, резистин оказывает существенное Диабетическая кардиомиопатия и резистин влияние на состояние экстрацеллюлярного матрикса миокарда [1,2]. Экстрацелюлярный матрикс является «фундамен-том», на котором сформирован кардиомиоцит.…”

“…При длительном сохране-нии структурного ремоделирования функционирова-ние сердечной мышцы постепенно нарушается [2], и в результате появляются клинические признаки сердеч-но-сосудистой недостаточности.…”