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

• Published in: PloS one Vol. 14; no. 1; p. e0210654
• Main Authors: Potenza, Maria Assunta, Sgarra, Luca, Nacci, Carmela, Leo, Valentina, De Salvia, Maria Antonietta, Montagnani, Monica
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2019; Public Library of Science (PLoS)
• Subjects: Activation; Adiponectin; Adiponectin - genetics; Adiponectin - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Apoptosis; Biology and Life Sciences; Blood pressure; Cardiac function; Cardiomyocytes; Cardiotonic agents; Cardiovascular disease; Deacetylation; Diabetes; Diastolic pressure; Heart; Heart attacks; Hypertension; Inhibitors; Ischemia; Ischemic Preconditioning - methods; Kinases; Laboratory animals; LKB1 protein; Male; Medical prognosis; Medical schools; Medicine and Health Sciences; Metabolism; Myocardial ischemia; Myocardial Reperfusion Injury - metabolism; Nitric oxide; Oncology; Pharmacology; Phosphorylation; Physiological aspects; Preconditioning; Protein hormones; Proteins; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion injury; Research and Analysis Methods; Resveratrol; Rodents; Signal Transduction - physiology; SIRT1 protein; Sirtuin 1 - metabolism; Tumor necrosis factor-TNF; Ventricle; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0210654

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. 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. 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.