Valsartan Prevented Neointimal Hyperplasia and Inhibited SRSF1 Expression and the TLR4-iNOS-ERK-AT1 Receptor Pathway in the Balloon-injured Rat Aorta.

Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta.Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartan-treated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p < 0.05). Moreover, valsartan increased the eNOS level and AT2 receptor mRNA and protein expression levels (all p < 0.05). Valsartan prevented neointimal hyperplasia and inhibited SRSF1 expression and the TLR4-iNOS-ERK-AT1 receptor pathway in the balloon-injured rat aorta.

Valsartan decreases neointimal hyperplasia in balloon-injured rat aortic arteries by upregulating HO-1 and inhibiting angiotensin II type 1 receptor.

AIMS: Upregulation of heme oxygenase (HO)-1 plays an important role in vascular protection. Valsartan attenuates neointimal hyperplasia in animal studies. The objective of this study was to examine the role of HO-1 and angiotensin II type 1 (AT1) receptor in the action of valsartan on neointimal hyperplasia in balloon-injured rat aortic arteries. MAIN METHODS: Thirty-six male Wistar rats were randomly divided into the following three groups with twelve rats in each group: control group, surgery (model) group, and valsartan group. Aortic balloon injury was performed to elicit endothelial denudation with a 2F balloon catheter. On days 14 and 28 after injury, blood was harvested to measure bilirubin levels. Aortic arteries were harvested for morphometry analysis, to determine angiotensin II (Ang II) level, and to analyze mRNA or protein expression. KEY FINDINGS: Compared with the control group, proliferation and intimal thickening of vascular smooth muscle cells (VSMCs) were obvious in the surgery group rats on days 14 and 28 after injury. Valsartan significantly reduced the proliferation and intimal thickening. Additionally, pretreatment with valsartan significantly reduced Ang II levels, AT1 receptor, and p38 mitogen-activated protein kinase (MAPK) expression. Valsartan increased HO-1 protein and mRNA expression, as well as increased serum bilirubin levels compared with the surgery group. SIGNIFICANCE: Valsartan treatment decreased neointimal hyperplasia in balloon-injured rats. The mechanism of action might be linked to the upregulation of HO-1, downregulation of AT1 receptor and inhibition of p38MAPK signal pathway.

Rosuvastatin attenuates atherosclerosis in rats via activation of scavenger receptor class B type I.

In order to investigate the effect and mechanism of action of rosuvastatin on atherosclerotic lesion in a Wistar rat model, 16 Wistar rats were fed a cholesterol-rich, vitamin D3 overload diet and underwent balloon injury of the aorta. One day prior to injury, half of the rats began rosuvastatin treatment (5mg/kg/d) via oral gavage. Eight control rats received a basal diet and sham operation. After 14 weeks of treatment, the animals were sacrificed. Blood was collected to measure lipid and angiotensin II (Ang II) levels and morphologic analysis was performed on the aorta. Scavenger receptor-class B type I (SR-BI), Ang II type-1 (AT1) receptor and phosphorylated extracellular signal regulated kinase 1/2 (p-ERK1/2) protein and mRNA levels were measured via Western blot and real time reverse transcriptase polymerase chain reaction, respectively. Spearman's rank correlation was utilized to examine the relationships between SR-BI and Ang II or AT1 receptor expression. The atherosclerosis model group demonstrated an increase in plasma lipid levels and aortic plaque formation. After 14 weeks of treatment with rosuvastatin, there was a significant decrease in plasma lipid and Ang II levels accompanied by an improvement in aortic lesions. Rosuvastatin increased the expression of SR-BI but significantly inhibited the expression of AT1 receptor and p-ERK1/2. SR-BI protein expression was inversely correlated with both the level of Ang II and expression of the AT1 receptor. In conclusion, rosuvastatin attenuates atherosclerosis in the Wistar rat model, and its anti-atherosclerotic activity may be through upregulation of SR-BI expression and inhibition of p-ERK1/2 levels and AT1 receptor expression.

Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats.

OBJECTIVE: To investigate the effects and mechanisms of rosuvastatin on angiotensin -converting enzyme 2 (ACE2) in the process of neointimal formation after vascular balloon injury in rats, and to explore the effects of ACE2 and rosuvastatin in restenosis. METHODS: Thirty-six Wistar rats were randomly allocated into three groups: control group (n = 12), surgery group (n = 12), and statin group (n = 12). Aortic endothelial denudation of rats was performed using 2F balloon catheters. At days 14 and 28 after injury, aortic arteries were harvested to examine the following. Intimal thickening was examined by hematoxylin and eosin staining. We measured angiotensin II (Ang II) and angiotensin 1-7 (Ang-[1-7]) levels by a radioimmunological method or enzyme-linked immunosorbent assay. Protein and mRNA expression of ACE2 and Ang II type 1 receptor (AT1) were investigated by immunohistochemistry, Western blots, and Reverse transcriptase-polymerase chain reaction (RT-PCR). We measured changes in proliferating cell nuclear antigen (PCNA) by immunohistochemistry. The level of phosphorylated extracellular signal regulated kinase 1/2 (P-ERK1/2) was evaluated by Western blotting. RESULTS: Proliferation of vascular smooth muscle cells (VSMC) and intimal thickening were higher at day 14 after vascular balloon injury in the surgery group compared with the control group. Proliferation of VSMC was decreased by day 28 after injury, while intimal thickening continued. With rosuvastatin treatment, the extent of VSMC proliferation and intimal thickening was reduced at day 14 and 28 after injury. Ang II and P-ERK levels were significantly increased, Ang-(1-7) levels were significantly decreased, mRNA and protein expressions of ACE2 were significantly decreased, and AT1 expression was significantly increased at days 14 and 28 after vascular balloon injury in the surgery group compared with the control group. PCNA expression was higher in the surgery group than in the control group, and it was significantly decreased after being given rosuvastatin. Expression of ACE2 mRNA and protein, and Ang-(1-7) levels were significantly increased, while AT1 expression and levels of Ang II and P-ERK were significantly decreased in the statin group compared with the surgery group. CONCLUSIONS: Expression of ACE2 mRNA and protein is decreased in the process of intimal thickening after balloon injury. The inhibitory effect of rosuvastatin on intimal thickening is related to upregulation of ACE2, an increase in Ang-(1-7), downregulation of AT1, and activation of the P-ERK pathway.