Key Points
- To determine the molecular mechanisms by which endothelin-1 (ET-1) and sodium hydrogen exchanger-1 (NHE-1) contribute to glucose-induced cardiomyocyte hypertrophy using an endothelial-myocyte co-culture model.
- Cultured rat ventricular cardiomyocytes alone and in co-culture with endothelial cells under high-glucose conditions.
- Treated cell models with the ET antagonist bosentan, the NHE-1 inhibitor cariporide, and protein kinase C (PKC) inhibitors to assess their effect on cell hypertrophy and hypertrophic markers (ANP, Agt, and iNOS).
- Assessed MAPK pathway activation and its downstream relationship with transcription factors NF-κB and AP-1.
- High glucose exposure induced cardiomyocyte hypertrophy and upregulated hypertrophic markers (ANP, Agt) and iNOS.
- Treatment with bosentan and cariporide prevented cardiomyocyte hypertrophy and marker upregulation, showing greater normalization in endothelial-myocyte co-cultures than in cardiomyocyte monocultures.
- Glucose-induced activation of MAPK acted upstream of NF-κB and AP-1 to drive hypertrophy and was successfully blocked by bosentan, cariporide, and PKC inhibition.
Structured PICO
PPopulationRat ventricular cardiomyocytes cultured in high glucose levels (alone or co-cultured with endothelial cells)
IInterventionBosentan (endothelin antagonist) and cariporide (NHE-1 inhibitor)
CComparatorHigh glucose without inhibitors
OOutcomeCardiomyocyte hypertrophy and expression of hypertrophic markers (ANP, Agt) and iNOSsurrogate
Endothelin-1 and NHE-1 mediate glucose-induced cardiomyocyte hypertrophy via MAPK activation, providing mechanistic insight into the pathogenesis of diabetic cardiomyopathy.