Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-gamma/Adiponectin Signalling

Alexios S. Antonopoulos; Marios Margaritis; Sander Verheule; Alice Recalde; Fabio Sanna; Laura Herdman; Costas Psarros; Hussein Nasrallah; Patricia Coutinho; Ioannis Akoumianakis; Alison C. Brewer; Rana Sayeed; George Krasopoulos; Mario Petrou; Akansha Tarun; Dimitris Tousoulis; Ajay M. Shah; Barbara Casadei; Keith M. Channon; Charalambos Antoniades

doi:10.1161/CIRCRESAHA.115.307856

Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-gamma/Adiponectin Signalling

Alexios S. Antonopoulos, Marios Margaritis, Sander Verheule, Alice Recalde, Fabio Sanna, Laura Herdman, Costas Psarros, Hussein Nasrallah, Patricia Coutinho, Ioannis Akoumianakis, Alison C. Brewer, Rana Sayeed, George Krasopoulos, Mario Petrou, Akansha Tarun, Dimitris Tousoulis, Ajay M. Shah, Barbara Casadei, Keith M. Channon, Charalambos Antoniades^*

^*Corresponding author for this work

Fysiologie

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Rationale: Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. Objective: To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. Methods and Results: EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase-derived O-2(-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O-2(-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O-2(-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ in EpAT. Conclusions: We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.

Original language	English
Pages (from-to)	842-855
Journal	Circulation Research
Volume	118
Issue number	5
DOIs	https://doi.org/10.1161/CIRCRESAHA.115.307856
Publication status	Published - 4 Mar 2016

Keywords

obesity
adipose tissue
adiponectin
oxidative stress
myocardium

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Antonopoulos, A. S., Margaritis, M., Verheule, S., Recalde, A., Sanna, F., Herdman, L., Psarros, C., Nasrallah, H., Coutinho, P., Akoumianakis, I., Brewer, A. C., Sayeed, R., Krasopoulos, G., Petrou, M., Tarun, A., Tousoulis, D., Shah, A. M., Casadei, B., Channon, K. M., & Antoniades, C. (2016). Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-gamma/Adiponectin Signalling. Circulation Research, 118(5), 842-855. https://doi.org/10.1161/CIRCRESAHA.115.307856

@article{99ca0e621d9c40029547004cbf082283,

title = "Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-gamma/Adiponectin Signalling",

abstract = "Rationale: Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. Objective: To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. Methods and Results: EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase-derived O-2(-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O-2(-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O-2(-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ in EpAT. Conclusions: We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.",

keywords = "obesity, adipose tissue, adiponectin, oxidative stress, myocardium",

author = "Antonopoulos, {Alexios S.} and Marios Margaritis and Sander Verheule and Alice Recalde and Fabio Sanna and Laura Herdman and Costas Psarros and Hussein Nasrallah and Patricia Coutinho and Ioannis Akoumianakis and Brewer, {Alison C.} and Rana Sayeed and George Krasopoulos and Mario Petrou and Akansha Tarun and Dimitris Tousoulis and Shah, {Ajay M.} and Barbara Casadei and Channon, {Keith M.} and Charalambos Antoniades",

year = "2016",

month = mar,

day = "4",

doi = "10.1161/CIRCRESAHA.115.307856",

language = "English",

volume = "118",

pages = "842--855",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "5",

}

Antonopoulos, AS, Margaritis, M, Verheule, S, Recalde, A, Sanna, F, Herdman, L, Psarros, C, Nasrallah, H, Coutinho, P, Akoumianakis, I, Brewer, AC, Sayeed, R, Krasopoulos, G, Petrou, M, Tarun, A, Tousoulis, D, Shah, AM, Casadei, B, Channon, KM & Antoniades, C 2016, 'Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-gamma/Adiponectin Signalling', Circulation Research, vol. 118, no. 5, pp. 842-855. https://doi.org/10.1161/CIRCRESAHA.115.307856

TY - JOUR

T1 - Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-gamma/Adiponectin Signalling

AU - Antonopoulos, Alexios S.

AU - Margaritis, Marios

AU - Verheule, Sander

AU - Recalde, Alice

AU - Sanna, Fabio

AU - Herdman, Laura

AU - Psarros, Costas

AU - Nasrallah, Hussein

AU - Coutinho, Patricia

AU - Akoumianakis, Ioannis

AU - Brewer, Alison C.

AU - Sayeed, Rana

AU - Krasopoulos, George

AU - Petrou, Mario

AU - Tarun, Akansha

AU - Tousoulis, Dimitris

AU - Shah, Ajay M.

AU - Casadei, Barbara

AU - Channon, Keith M.

AU - Antoniades, Charalambos

PY - 2016/3/4

Y1 - 2016/3/4

N2 - Rationale: Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. Objective: To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. Methods and Results: EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase-derived O-2(-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O-2(-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O-2(-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ in EpAT. Conclusions: We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.

AB - Rationale: Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. Objective: To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. Methods and Results: EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase-derived O-2(-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O-2(-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O-2(-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-gamma-mediated upregulation of ADIPOQ in EpAT. Conclusions: We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.

KW - obesity

KW - adipose tissue

KW - adiponectin

KW - oxidative stress

KW - myocardium

U2 - 10.1161/CIRCRESAHA.115.307856

DO - 10.1161/CIRCRESAHA.115.307856

M3 - Article

C2 - 26838789

SN - 0009-7330

VL - 118

SP - 842

EP - 855

JO - Circulation Research

JF - Circulation Research

IS - 5

ER -