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.

Figure 1

The mTORC1-mediated increase in AT2R expression can lead to AT2R-mediated inhibition of mTOR substrates and modulate mTORC1 signaling.

Figure 2

(a) Locations of miRNA binding sites on 2287bp S6K1 mRNA. Location of open reading frame (ORF) is marked. (b) Representative autoradiogram showing S6K1 protein levels in ZO and ZL LV tissues. *P < 0.05 for ZO versus ZL LV tissue. (c) % increase in miRNA levels in ZO LV tissues versus ZL LV tissues (n = 3 for each group, P for ZO versus ZL < 0.05).

Figure 3

Location of rno-mir-200c on the chromosome 4 of rat with associated QTLs and protein coding regions as shown in Ensemble Rattus norvegicus version 63.34. rno-mir-200c is associated with Heart rate QTL 13.

Figure 4

Established and putative signaling mechanisms activated by chronic alcohol consumption are superimposed on the signaling mechanisms activated by overnutrition to show how alcohol may exacerbate cardiac diseases in the setting of overnutrition. Dotted purple lines show alcohol mediated upregulation, and dotted orange lines show alcohol-induced inhibition of different signaling components.