Leptin and endothelin-1 mediated increased extracellular matrix protein production and cardiomyocyte hypertrophy in diabetic heart disease.
BACKGROUND
We investigated the role of leptin and its interaction with endothelin 1 (ET-1) in fibronectin (FN) synthesis and cardiomyocyte hypertrophy, two characteristic features of diabetic cardiomyopathy.


METHODS
Endothelial cells [human umbilical vein endothelial cells (HUVECs)] were examined for FN production and neonatal rat cardiomyocytes for hypertrophy, following incubation with glucose, ET-1, leptin and specific blockers. FN, ET-1, leptin and leptin receptors mRNA expression and FN protein were measured. Myocytes were also morphometrically examined. Furthermore, hearts from streptozotocin-diabetic rats were analysed.


RESULTS
Glucose caused increased FN mRNA and protein expression in HUVECs and cardiomyocytes hypertrophy along with upregulation of ET-1 mRNA, leptin mRNA and protein. Glucosemimetic effects were seen with leptin and ET-1. Leptin receptor antagonist (leptin quadruple mutant) and dual endothelin A endothelin B (ETA/ETB) receptor blocker bosentan normalized such abnormalities. Hearts from the diabetic animals showed hypertrophy and similar mRNA changes.


CONCLUSIONS
These data indicate that in diabetes increased FN production and cardiomyocyte hypertrophy may be mediated through leptin with its interaction with ET-1.
Majumdar
Pijush
P
Departments of Pathology and Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, Ontario, Canada.
Chen
Shali
S
George
Biju
B
Sen
Subhrojit
S
Karmazyn
Morris
M
Chakrabarti
Subrata
S
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D020738:Leptin / Q000235:genetics / Q000502:physiology*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin