Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

Abstract

In vivo evidence for the pleiotropic effects of simvastatin on the nitric oxide synthase system is limited. Aims: To determine if simvastatin can affect the endothelial nitric oxide synthase cascade. Methods: New Zealand white rabbits (n=15) were divided: Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine (M) plus 0.5% cholesterol (C) and 5% peanut oil (atherogenic diet); Group 3 received the same diet as the MC group plus 5 mg/kg/ day simvastatin (S) orally (MCS). After 4 weeks, the abdominal aorta was collected and analyzed.

3‐Methylcholanthrene/Aryl‐Hydrocarbon Receptor‐Mediated Hypertension Through eNOS Inactivation

“…Consistent with the results of previous studies reporting that dynein disrupts eNOS dimerization (Hemmens et al, ), we observed that 3‐MC‐mediated upregulation of dynein expression correlated with a decrease in the ratio of eNOS dimer to monomer. Our results support the evidence of the interwoven relationship between Rho/Rock and Akt/PKB and a feedback loop in the regulation of eNOS activation (Ming et al, ; Rikitake and Liao, ; Arora et al, ). In our previous study, wortmannin, a PI3K/Akt inhibitor, mimicked the effects of 3‐MC and increased 3‐MC‐mediated RhoA/PTEN activation in MCVECs (Hsu et al, ); however, YS‐49, a PI3K/Akt activator, reduced the effects through inactivating RhoA (a negative feedback loop).…”

“…However, the underlying mechanism through which statin increases eNOS activity remains unclear. In vivo experimental studies on rabbits have reported that simvastatin does not directly affect eNOS or eNOS phosphorylation but downregulates caveolin‐1 expression (Arora et al, ). By contrast, our study results indicated that statins increase eNOS and its phosphorylation and downregulate caveolin‐1 expression.…”

Lower levels of Caveolin-1 and higher levels of endothelial nitric oxide synthase are observed in abdominal aortic aneurysm patients treated with simvastatin

“…In addition, a decrease in Cav-1 and an increase in eNOS has been reported in endothelial tissue rather than in smooth muscle cells in rabbits on a high-fat diet following simvastatin treatment (Arora et al, 2012); however, no change in eNOS phosphorylation was detected, suggesting a possible role might be played by other mechanisms related to the antioxidative role of statins or accumulation of cGMP, which is an indicator of eNOSdependant NO bioavailability (Meda et al, 2010;Piechota-Polanczyk et al, 2012).…”

“…Cav-1 expression is positively correlated with atherosclerosis and obesity (Singh et al, 2011); it has been reported to modulate MMP-2 activity in heart tissue (Chow et al, 2007) and influence AAA formation through its functional relationship with angiotensin II (Ang II) receptors (Kowalska et al, 2016;Takayanagi et al, 2014). It might also act as an immunomodulatory agent via its action on NF-κB and TLR4 (Mirza et al, 2010), and may influence the effect of simvastatin (Almansob et al, 2012): simvastatin has been found to potentially downregulate Cav-1 expression and increase eNOS expression in the abdominal aorta of animals (Arora et al, 2012). Nevertheless, it is not known whether statins might cause a similar effect in AAA patients.…”

Alamandine reverses hyperhomocysteinemia‐induced vascular dysfunction via PKA‐dependent mechanisms

“…Images (at 200× and 400× magnification) of tissue sections were taken by Leica DFC450 program from n = 3 rabbits (as only 3 rabbits were rescued after organ bath procedures). The endothelium and the media of HHcy and control incubated rings were traced using ribbon tool from MCID program to measure the reciprocal unit of color intensity/proportional area of the chromogen stain (brown in color) as described previously . Therefore, the measure of color intensity: proportional area ratio is arbitrary units, and as such results are in arbitrary units.…”