Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction.
BACKGROUND
Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes.


RESULTS
Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a.


CONCLUSIONS
Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.
Sabrina
S
Greulich
Bujar
B
Maxhera
Guy
G
Vandenplas
Daniella Herzfeld
DH
de Wiza
Konstantinos
K
Smiris
Heidi
H
Mueller
Jessica
J
Heinrichs
Marcel
M
Blumensatt
Claude
C
Cuvelier
Payam
P
Akhyari
Johannes B
JB
Ruige
D Margriet
DM
Ouwens
Juergen
J
Eckel
D028341:Activins / Q000378:metabolism / Q000494:pharmacology*; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D042702:Angiopoietin-2 / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D010496:Pericardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D042702:Angiopoietin-2; D017077:Culture Media, Conditioned; D007328:Insulin; C422405:activin A; D028341:Activins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium