Angiotensin-(1–7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin–p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin–c-Jun N-terminal kinase pathway in vitro

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Angiotensin-(1–7) (Ang-[1–7]), recognized as a new bioactive peptide in the renin–angiotensin system, shows biological and pharmacological properties in diabetic cardiovascular diseases. The leptin-induced p38 mitogen-activated protein kinase (MAPK) pathway has been reported to contribute to high glucose (HG)-induced injury. In the present study, we showed the mechanism of how Ang-(1–7) can protect against HG-stimulated injuries in H9c2 cells.

Materials and Methods

H9c2 cells were treated with 35 mmol/L glucose (HG) for 24 h to establish a model of HG-induced damage. Apoptotic cells were observed by Hoechst 33258 staining. Cell viability was analyzed by cell counter kit-8. The expression of protein was detected by western blot. Reactive oxygen species was tested by 2′,7′-dichlorodihydrofluorescein diacetate staining. Mitochondrial membrane potential was measured by 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide staining.


The present results showed that treating H9c2 cells with HG obviously enhanced the expressions of both the leptin and phosphorylated (p)-MAPK pathway. However, the overexpression levels of leptin and p-p38 MAPK/p-extracellular signal-regulated protein kinase 1/2 (ERK1/2), but not p-c-Jun N-terminal kinase, were significantly suppressed by treatment of the cells with Ang-(1–7). Additionally, leptin antagonist also markedly suppressed the overexpressions of p38 and ERK1/2 induced by HG, whereas leptin antagonist had no influence on the overexpression of c-Jun N-terminal kinase. More remarkable, Ang-(1–7), leptin antagonist, SB203580 or SP600125, respectively, significantly inhibited the injuries induced by HG, such as the increased cell viability, decreased apoptotic rate, reduction of ROS production and increased mitochondrial membrane potential. Furthermore, the overexpressions of p38 MAPK, ERK1/2 and leptin were suppressed by N-actyl-L-cystine.


The present findings show that Ang-(1–7) protects from HG-stimulated damage as an inhibitor of the reactive oxygen species–leptin–p38 MAPK/ERK1/2 pathways, but not the leptin–c-Jun N-terminal kinase pathway in vitro.

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