Abstract
Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide mainly generated from cleavage of AngI and AngII, possesses physiological and pharmacological properties, including anti-inflammatory and antidiabetic properties. Activation of the phosphoinositide 3-kinase and protein kinase B (PI3K/Akt) signaling pathway has been confirmed to participate in cardioprotection against hyperglycaemia-induced injury. The aim of the present study was to test the hypothesis that Ang-(1-7) protects H9c2 cardiomyoblast cells against high glucose (HG)-induced injury by activating the PI3K/Akt pathway. To examine this hypothesis, H9c2 cells were treated with 35 mmol/l (mM) glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. The cells were co-treated with 1 μmol/l (μM) Ang-(1-7) and 35 mM glucose. The findings of the present study demonstrated that exposure of H9c2 cells to HG for 24 h markedly induced injury, as evidenced by an increase in the percentage of apoptotic cells, generation of reactive oxygen species and level of inflammatory cytokines, as well as a decline in cell viability and mitochondrial luminosity. These injuries were significantly attenuated by co-treatment of the cells with Ang-(1-7) and HG. In addition, PI3K/Akt phosphorylation was suppressed by HG treatment, but this effect was abolished when the H9c2 cells were co-treated with Ang-(1-7) and HG. Furthermore, the cardioprotection of Ang-(1-7) against HG-induced injury in H9c2 cardiomyoblasts was highly attenuated in the presence of either D-Ala7-Ang-(1-7) (A-779, an antagonist of the Mas receptor) or LY294002 (an inhibitor of PI3K/Akt). In conclusion, the present study provided new evidence that Ang-(1-7) protects H9c2 cardiomyoblasts against HG-induced injury by activating the PI3K/Akt signaling pathway.
Highlights
Diabetes severely affects human health, and epidemiological studies have reported that the number of diabetic patients is expected to reach 592 million worldwide by 2035 (1)
The high glucose (HG) (35 mM glucose)-induced H9c2 cardiomyoblast injury model was used to investigate the cardioprotective effects of Ang-(1-7) against HG-induced cardiomyocyte injury and the underlying mechanisms
Caspase-1, -3 and -12 are known to be involved in cell apoptosis and inflammatory response (29,30,45-47); we investigated the expression of these proteins and found that HG treatment significantly increased their levels, further confirming that HG treatment may trigger apoptosis and inflammation in H9c2 cardiomyoblasts
Summary
Diabetes severely affects human health, and epidemiological studies have reported that the number of diabetic patients is expected to reach 592 million worldwide by 2035 (1). Diabetes is tightly associated with both microvascular (including neuropathy, nephropathy and retinopathy) and macrovascular (including cardiovascular diseases) complications (2-6). DCM is generally considered to be manifested by a series of structural and functional anomalies in the myocardium of diabetic patients, including myocardial fibrosis, impaired diastolic and systolic contractility, cardiomyocyte hypertrophy, cardiac autonomic neuropathy and apoptosis (8-11). Hyperglycaemia is the key element of diabetes, and plays a crucial role in the evolution of DCM (11,12). Accumulating reports have revealed that multifarious factors may contribute to hyperglycaemia-induced myocardial damage, including reactive oxygen species (ROS) generation (13-18), insufficiency of antioxidant systems (16-21) and mitochondrial dysfunction (13,21,22). Cardiac inflammatory reactions, characterized by increased levels of pro-inflammatory cytokines, may play an important part in the manifestation of DCM (23-25). The pathogenesis of hyperglycaemia-induced cardiomyocyte injury has not been fully elucidated
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