Simvastatin Mitigates Apoptosis and Transforming Growth Factor-Beta Upregulation in Stretch-Induced Endothelial Cells

Portal hypertension is a common clinical symptom of digestive disorders. With an increase in portal pressure, the portal vein will continue to dilate. We aimed to determine whether continuous stretch induced by portal hypertension may impair the function of endothelial cells (ECs) in the portal vein and aggravate the progress of portal hypertension and explore its mechanism. ECs were cultured on an elastic silicone membrane and subjected to continuous uniaxial stretch. Apoptosis and expression of TGF-β in ECs under stretch were measured. We found that sustained stretch induced the apoptosis of ECs in a stretch length-dependent manner. Compared with the control, continuous stretch increased the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and damaged the mitochondria, resulting in an evident increase in reactive oxygen species (ROS) levels; pretreatment with gp91ds-tat or MitoTEMPO decreased the ROS level in the intracellular levels. N-acetyl-cysteine (NAC) treatment before stretch not only reduced ROS levels but also mitigated the apoptosis of ECs; simvastatin had similar effects through targeting NOX2 and mitochondria. During the stretch, the phosphorylation of p38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB) was obviously increased; pretreatment with P38MAPK or JNK inhibitors decreased the phosphorylation of NF-κB and TGF-β expression. Pyrrolidine dithiocarbamate (PDTC) treatment before stretch also reduced TGF-β expression. After pretreatment with NAC, the phosphorylation of P38MAPK, JNK, and NF-κB and TGF-β expressions in ECs under stretch was suppressed; similar results were observed in simvastatin-treated ECs. This study demonstrated that simvastatin could mitigate EC apoptosis and TGF-β upregulation induced by continuous stretch by reducing the level of ROS.