title: Cardiac insulin resistance and microRNA modulators.
abstract: Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS), and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO) rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.
authors: Department of Internal Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
authors: Lakshmi
authors: L
authors: Pulakat
authors: Annayya R
authors: AR
authors: Aroor
authors: Rukhsana
authors: R
authors: Gul
authors: James R
authors: JR
authors: Sowers
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000378:metabolism*; D046912:Multiprotein Complexes; D009206:Myocardium / Q000378:metabolism*; D044343:Overnutrition / Q000150:complications / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007328:Insulin; D035683:MicroRNAs; D046912:Multiprotein Complexes; D011506:Proteins; D011945:Receptors, Angiotensin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1