Role of endothelin-1, sodium hydrogen exchanger-1 and mitogen activated protein kinase (MAPK) activation in glucose-induced cardiomyocyte hypertrophy.
BACKGROUND
Cardiac hypertrophy is a key structural feature of diabetic cardiomyopathy. Previous studies have shown that diabetes-induced endothelin-1 (ET-1) and sodium hydrogen exchanger-1 (NHE-1) mediate structural and functional deficits in the heart. In order to gain a mechanistic understanding of the role of ET-1 and NHE-1 in cardiomyocyte hypertrophy, we have utilized an in vitro endothelial-myocyte co-culture system to reveal cellular interactions that may arbitrate cardiomyocyte deficits in diabetes.


RESULTS
Rat ventricular cardiomyocytes were cultured in high glucose levels, which caused cellular hypertrophy. Hypertrophic markers, atrial natruritic peptide (ANP) and angiotensinogen (Agt), as well as inducible nitric oxide synthase (iNOS) were upregulated by high glucose. Treatment of cells with ET antagonist bosentan and NHE-1 inhibitor cariporide prevented glucose-induced cardiomyocyte hypertrophy and expression of ANP, Agt, and iNOS. Bosentan and cariporide treatment of cardiomyocytes co-cultured with endothelial cells produced a more pronounced normalization of glucose-induced changes as compared to cardiomyocyte cultured alone. To further explore the signaling mechanisms involved, we investigated the mitogen activated protein kinase (MAPK) pathway and its cross-interaction with signaling proteins known to be altered in diabetes. Our results indicate that MAPK activation is associated with cardiomyocyte hypertrophy and is inhibited by bosentan, cariporide, as well as protein kinase C inhibiton. Furthermore, MAPK activation was found to be upstream of the transcription factors, nuclear factor-kappaB and activating protein-1.


CONCLUSIONS
These results demonstrate that ET-1 and NHE-1 may mediate cardiomyocyte hypertrophy via MAPK activation and provide an insight into the pathogenesis of diabetic cardiomyopathy.
Chen
Shali
S
Department of Pathology, University of Western Ontario, Ontario, Canada.
Khan
Zia A
ZA
Karmazyn
Morris
M
Chakrabarti
Subrata
S
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D006984:Hypertrophy; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*; D014471:Umbilical Veins
D019332:Endothelin-1; D017923:Sodium-Hydrogen Exchangers; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose