Activation of AMPK/SIRT1 axis is required for adiponectin-mediated preconditioning on myocardial ischemia-reperfusion (I/R) injury in rats

PLoS One. 2019 Jan 17;14(1):e0210654. doi: 10.1371/journal.pone.0210654. eCollection 2019.

Abstract

Background: Adiponectin (AD) cardioprotective activities are mediated by AMPK, a fuel-sensing molecule sharing common targets and cellular activities with SIRT-1. Whether AD preconditioning may involve SIRT-1 activity is not known; however, the protective role of SIRT-1 during ischemia and the potential interplay between AMPK and SIRT-1 suggest this possibility.

Methods: Isolated hearts from male Sprague-Dawley rats (n = 85) underwent ischemia/reperfusion (I/R, 30/180 min). Preconditioning with resveratrol (RSV, SIRT-1 activator) was compared to preconditioning with AD alone, or in combination with compound C (CC, AMPK inhibitor) or sirtinol (STN, SIRT-1 inhibitor). For each heart, left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (dLVP), coronary flow (CF) and left ventricular infarct mass (IM) were measured, together with the phosphorylation/activation status of AMPK, LKB1, eNOS and SIRT-1, at the beginning (15 min) and at the end (180 min) of reperfusion.

Results and conclusions: When compared to I/R, both RSV and AD improved cardiac function and reduced IM (p < 0.01, p < 0.05, respectively). Cardioprotective effects of AD were completely reversed in the AD+CC group, and significantly attenuated in the AD+STN group. Both RSV and AD increased eNOS, AMPK and LKB1 phosphorylation (for each parameter: p < 0.05 vs. I/R, in both RSV and AD treatment groups) at 15 min of reperfusion, and SIRT-1 activity at the end of reperfusion (p < 0.01, p < 0.05 vs. I/R, respectively). Interestingly, AD-mediated phosphorylation of AMPK and LKB1, and SIRT-1 deacetylation activity was markedly reduced in both the AD+CC and AD+STN groups (p < 0.05 vs. AD). Thus, AD-mediated cardioprotection requires both AMPK and SIRT-1 signaling pathways, that act as a component of a cycle and regulate each other's activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adiponectin / genetics
  • Adiponectin / metabolism*
  • Animals
  • Ischemic Preconditioning / methods*
  • Male
  • Myocardial Reperfusion Injury / metabolism
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Sirtuin 1 / metabolism*

Substances

  • Adiponectin
  • AMP-Activated Protein Kinases
  • Sirtuin 1

Grants and funding

This work was supported, in part, by the Italian Ministry of University (MIUR) research grant award (PRIN 2010YK7Z5K_008) to M.M. and, in part, by the University of Bari Research funds (CUP H96J15001610005) to M.M.